Novel thyroid receptor ligands and method II

ABSTRACT

New thyroid receptor ligands are provided which have general formula (I) in which: n is an integer from 0 to 4; R 1  is halogen, trifluoromethyl, or alkyl of 1 to 6 carbons or cycloalkyl of 3 to 7 carbons; R 2  and R 3  are the same or differential hydrogen, halogen, alkyl of 1 to 4 carbons or cycloalkyl of 3 to 5 carbons, at least one of R 2  and R 3  being other than hydrogen; R 4  is a carboxylic acid thereof; or when n is equal to or greater than one, R 4  may be heteroaromatic moiety which may be substituted or unsubstituted, or an amine (NR′R″). R 5  is hydrogen or an acyl (such as acetyl or benzoyl) or other group capable of bioconversion to generate the free phenol structure (wherein R 5 —H). In addition, a method is provided for preventing, inhibiting or treating a disease associated with metabolism dysfunction or which is dependant upon the expression of a T 3  regulated gene, wherein a compound as described above is administered in a therapeutically effective amount. Examples of such diseases associated with metabolism dysfunction or are dependent upon the expression of a T 3  regulated gene include obesity, hypercholesterolemia, atherosclerosis, cardiac arrhythmias, depression, osteoporosis, hypothyroidism, goiter, thyroid cancer as well as glaucoma, congestive heart failure and skin disorders.

FIELD OF THE INVENTION

This invention relates to novel compounds which are thyroid receptorligands, and are preferably selective for the thyroid hormone receptorβ, to methods of preparing such compounds and to methods for using suchcompounds such as in the regulation of metabolism.

BACKGROUND OF THE INVENTION

While the extensive role of thyroid hormones in regulating metabolism inhumans is well recognized, the discovery and development of new specificdrugs for improving the treatment of hyperthyroidism and hypothyroidismhas been slow. This has also limited the development of thyroid hormoneagonists and antagonists for treatment of other important clinicalindications, such as hypercholesterolemia obesity and cardiacarrhythmias.

Thyroid hormones affect the metabolism of virtually every cell of thebody. At normal levels. These hormones maintain body weight themetabolic rate, body temperature, and mood, and influence sent lowdensity lipoprotein (LDL) levels. Thus, in hypothyroidism there isweight gain high levels of LDL cholesterol, and depression. In excesswith hyperthyroidism, these hormones lead to weight loss,hypermetabolism, lowering of serum LDL levels, cardiac arrhythmias,heart failure, muscle weakness bone loss in postmenopausal women, andanxiety.

Thyroid hormones are currently used primarily as replacement therapy forpatients with hypothyroidism. Therapy with L-thyroxine returns metabolicfunctions to normal and can easily be monitored with routine serummeasurements of levels of thyroid-stimulating hormone (TSH), thyroxine(3.5.3′.5′-tetraiodo-L-thyronine, or T₄) and triiodothyronine(3.5.3′-triiodo-L-thyronine, or T₃). However, replacement therapy,particularly in older individuals is limited by certain of thedeleterious effects of thyroid hormones

In addition, some effects of thyroid hormones may be therapeuticallyuseful in non-thyroid disorders if adverse effects can be minimized oreliminated. These potentially useful influences include weightreduction, lowering of serum LDL levels, amelioration of depression andstimulation of bone formation. Prior attempts to utilize thyroidhormones pharmacologically to treat these disorders have been limited bymanifestations of hyperthyroidism and in particular by cardiovasculartoxicity.

Development of specific and selective thyroid hormone receptor agonistscould lead to specific therapies for these common disorders whileavoiding the cardiovascular and other toxicities of native thyroidhormones. Tissue-selective thyroid hormone agonists may be obtained byselective tissue uptake or extrusion, topical or local delivery,targeting to cells through other ligands attached to the agonist andtargeting receptor subtypes. Thyroid hormone receptor agonists thatinteract selectively with the β-form of the thyroid hormone receptoroffers an especially attractive method for avoiding cardio-toxicity.

Thyroid hormone receptors (TRs) are, like other nuclear receptors,single polypeptide chains. The various receptor forms appear to beproducts of two different genes α and β. Further isoform differences aredue to the fact that differential RNA processing results in at least twoisoforms from each gene. The TRα₁, TRβ₁ and TRβ₂ isoforms bind thyroidhormone and act as ligand-regulated transcription factors. In adults,the TRβ₁ isoform is the most prevalent form in most tissues, especiallyin the liver and muscle. The TRα₂ isoform is prevalent in the pituitaryand other parts of the central nervous system, does not bind thyroidhormones, and acts in many contexts as a transcriptional repressor. TheTRα₁ isoform is also widely distributed, although its levels aregenerally lower than those of the TRβ₁ isoform. This isoform may beespecially important for development. Whereas many mutations in the TRβgene have been found and lead to the syndrome of generalized resistanceto thyroid hormone mutations leading to impaired TRα function have notbeen found.

A growing body of data suggest that many or most effects of thyroidhormones on the heart, and in particular on the heart rate and rhythm,are mediated through the α-form of the TRα1 isoform, whereas mostactions of the hormone such as on the liver, muscle and other tissuesare mediated more through the β-forms of the receptor. Thus, aTRβ-selective agonist might not elicit the cardiac rhythm and rateinfluences of the hormones but would elicit many other actions of thehormones. It is believed that the α-form of the receptor is the majordrive to heart rate for the following reasons:

-   -   1) tachycardia is very common in the syndrome of generalized        resistance to thyroid hormone in which there are defective        TRβ-forms, and high circulating levels of T₄ and T₃;    -   2) there was a tachycardia in the only described patient with a        double deletion of the TRβ gene (Takeda et al, J. Clin.        Endrocrinol. & Metab. 1992, Vol. 74, p. 49);    -   3) a double knockout TRα gene (but not β-gene) in the mouse has        a slower pulse than control mice; and,    -   4) western blot analysis of human myocardial TRs show presence        of the TRα₁, TRα₂, and TRβ₂ proteins, but not TRβ₁.

If these indications are correct, then a TRβ-selective agonist could beused to mimic a number of thyroid hormone actions, while having a lessereffect on the heart. Such a compound may be used for: (1) replacementtherapy in elderly subjects with hypothyroidism who are at risk forcardiovascular complications; (2) replacement-therapy in elderlysubjects with subclinical hypothyroidism who are at risk forcardiovascular complications; (3) obesity; (4) hypercholesterolemia dueto elevations of plasma LDL levels; (5) depression; and, (6)osteoporosis in combination with a one resorption inhibitor.

DESCRIPTION OF THE INVENTION

In accordance with the present invention, compounds are provided whichare thyroid receptor ligands, and have the general formula I:

in which:

-   -   n is an integer from 0 to 4;    -   R₁ is halogen, trifluoromethyl, or alkyl of 1 to 6 carbons or        cycloalkyl of 3 to 7 carbons;    -   R₂ and R₃ are the same or different and are hydrogen, halogen,        alkyl of 1 to 4 carbons or cycloalkyl of 3 to 5 carbons, at        least one of R₂ and R₃ being other than hydrogen;    -   R₄ is a heteroaromatic moiety which may be substituted or        unsubstituted and is linked to (CH₂)_(n) via a nitrogen atom or        a carbon atom; an amine (NR′R″), including those in which the        amine is derived from an alpha amino acid of either natural (L)        or unnatural (D) stereochemistry; an acylsulphonamide        (CONHSO₂R′) or a carboxylic acid amide (CONR′R″) in which the        amine portion of the carboxylic amide can be derived from an        achiral or a L or D alpha amino acid such as when the general        structure —CONR′R″ can be represented by        and R′, R″, R′″ and R″′ are the same or different and are        independently selected from hydrogen, alkyl, aryl and        heteroaryl, substituted or unsubstituted, and R* may be        hydrogen, alkyl, aryl and heteroaryl, substituted or        unsubstituted, and may also be any of the side chains found in        the naturally occuring alpha-amino acids and their analogs,        including those examples wherein R′ and R* are connected to form        4 to 8-membered rings (such as when R′ and R* comprise        consecutive —(CH₂)— groups to form proline or homoproline); and        with the proviso that when n equals zero (n=0), then R₄ can only        be a carboxylic acid amide or an acylsulphonamide.

R₅ is hydrogen or an acyl (such as acetyl or benzoyl) or other groupcapable of bioconversion to generate the free phenol structure (whereinR₅═H);

-   -   including all stereoisomers thereof, prodrug esters thereof, and        pharmaceutically acceptable salts thereof.

In addition, in accordance with the present invention, a method forpreventing, inhibiting or treating a disease associated with metabolismdysfunction or which is dependent upon the expression of a T₃ regulatedgene is provided, wherein a compound of formula I is administered in atherapeutically effective amount. The compound of formula I ispreferably an agonist that is preferably selective for the thyroidhormone receptor-beta. Examples of such diseases associated withmetabolism dysfunction or are dependent upon the expression of a T₃regulated gene are set out hereinafter and include obesity,hypercholesterolemia, atherosclerosis, cardiac arrhythmias, depression,osteoporosis, hypothyroidism, goiter, thyroid cancer as well as glaucomaand congestive heart failure.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instances.

The term “thyroid receptor ligand” as used herein is intended to coverany moiety which binds to a thyroid receptor. The ligand may act as anagonist, an antagonist, a partial agonist or a partial antagonist.

The term “aliphatic hydrocarbon(s) as used herein refers to acyclicstraight or branched chain groups which include alkyl, alkenyl oralkynyl groups.

The term “aromatic hydrocarbon(s) as used herein refers to groupsincluding aryl groups as defined herein.

The term “heteroaryl” or “heteroaromatic moiety” as used herein alone oras a part of another group refers to a 5- or 6-membered aromatic ringwhich includes 1, 2, 3, or 4 heteroatoms, one of which must be anitrogen atom; the other heteroatoms when present may be nitrogen,oxygen or sulfur, and such rings may be fused to another aryl orheteroaryl ring, and includes possible N-oxides. The heteroaryl groupmay optionally include 1 to 4 substituents such as aryl, alkyl, alkenyl,alkynyl, cycloalkyl, hydroxy, cyano, nitro, amino and/or carboxyl, andincluding the following

and the like.

Unless otherwise indicated, the term “lower alkyl”, “alkyl” or “alk” asemployed herein alone or as part of another group includes both straightand branched chain hydrocarbons, containing 1 to 12 carbons (in the caseof alkyl or alk), in the normal chain, preferably 1 to 4 carbons, suchas methyl, ethyl, propyl, isopropyl, butyl, t-butyl, or isobutyl,pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, which may beoptionally substituted with 1 to 4 substituents which may include alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, hydroxy, cyano, nitro,amino and/or carboxyl.

The term “aryl” as employed herein alone or as part of another grouprefers to monocyclic and bicyclic aromatic groups containing 6 to 10carbons in the ring portion (such as phenyl or naphthyl including1-naphthyl and 2-naphthyl) and may be optionally substituted throughavailable carbon atoms with 1, 2, or 3 groups selected from hydrogen,halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl,trifluoromethoxy, alkynyl, hydroxy, amino, nitro, cyano and carboxylicacids.

Unless otherwise indicated, the term “lower alkenyl” or “alkenyl” asused herein by itself or as part of another group refers to straight orbranched chain radicals of 2 to 12 carbons, preferably 2 to 5 carbons,in the normal chain, which include one to six double bonds in the normalchain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl,3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl,3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, and the like,which may be substituted as in the case of “alkyl”.

Unless otherwise indicated, the term “lower alkynyl” or “alkynyl” asused herein by itself or as part of another group refers to straight orbranched chain radicals of 2 to 12 carbons, preferably 2 to 8 carbons,in the normal chain, which include one triple bond in the normal chain,such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl,2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl,3-nonynyl, 4-decynyl, 3-undecynyl, 4-dodecynyl and the like, which maybe substituted as in the case of “alkyl”.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group includes saturated cyclic hydrocarbongroups or partially unsaturated (containing 1 or 2 double bonds) cyclichydrocarbon groups, containing one ring and a total of 3 to 7 carbons,preferably 3 to 5 carbons, forming the ring, which includes cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl andcyclohexenyl, which may be substituted as in the case of “alkyl”.

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to chlorine, bromine, fluorine, and iodine as well as CF₃,with chlorine or bromine being preferred.

The compounds of formula I can be present as salts, in particularpharmaceutically acceptable salts. If the compounds of formula I have,for example, at least one basic center, they can form acid additionsalts. These are formed, for example, with strong inorganic acids, suchas mineral acids, for example sulfuric acid, phosphoric acid or ahydrohalic acid, with strong organic carboxylic acids, such asalkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted orsubstituted, for example, by halogen, for example acetic acid, such assaturated or unsaturated dicarboxylic acids, for example oxalic,malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, suchas hydroxycarboxylic acids, for example ascorbic, glycolic, lactic,malic, tartaric or citric acid, such as amino acids, (for exampleaspartic or glutamic acid or lysine or arginine), or benzoic acid, orwith organic sulfonic acids, such as (C₁-C₄) alkyl or arylsulfonic acidswhich are unsubstituted or substituted, for example by halogen, forexample methyl- or p-toluene-sulfonic acid. Corresponding acid additionsalts can also be formed having, if desired, an additionally presentbasic center. The compounds of formula I having at least one acid group(for example COOH) can also form salts with bases. Suitable salts withbases are, for example, metal salts, such as alkali metal or alkalineearth metal salts, for example sodium, potassium or magnesium salts, orsalts with ammonia or an organic amine, such as morpholine,thiomorpholine, piperidine, pyrrolidine, a mono, di or triloweralkylamine, for example ethyl, tertbutyl, diethyl, diisopropyl,triethyl, tributyl or dimethyl-propylamine, or a mono, di or trihydroxylower alkylamine, for example mono, di or triethanolamine. Correspondinginternal salts may furthermore be formed. Salts which are unsuitable forpharmaceutical uses but which can be employed, for example, for theisolation or purification of free-compounds I or their pharmaceuticallyacceptable salts, are also included.

Preferred salts of the compounds of formula I which include a basicgroups include monohydrochloride, hydrogensulfate, methanesulfonate,phosphate or nitrate.

Preferred salts of the compounds of formula I which include an acidgroup include sodium, potassium and magnesium salts and pharmaceuticallyacceptable organic amines.

Preferred are compounds of the invention of formula I wherein R₁ isisopropyl;

-   -   R₂ and R₃ are independently halogen such as bromo or chloro; or

-   R₂ and R₃ are each methyl or one is methyl and the other is ethyl;    -   or one of R₂ and R₃ is halogen such as bromo or chloro, and the        other is alkyl such as methyl, or hydrogen; and    -   n is 0, 1 or 2;    -   R₄ is carboxylic acid derivative of the type: amides,        acylsulphonamides or an amide formed from an amino acid residue;        and    -   R₅ is hydrogen.

The most preferred compounds have the structures:

-   -   and other preferred compounds of the invention have the        structures:    -   wherein R₁=isopropyl, methyl, ethyl, tertiary-butyl,        cyclopentyl, cyclohexyl; R₂ and R₃ may be independently selected        from Br, Cl and Me; R* may be hydrogen, alkyl, cycloalkyl, aryl        and heteroaryl; * denotes either D or L stereochemistry; and R′        and is selected from hydrogen, lower alkyl, especially ethyl and        methyl or where the group COOR′ represents prodrug ester forms        known in the art such as pivaloyloxymethyl or dioxolenylmethyl.        Such prodrug esters are described in standard references such as        Chapter 31, written by Camille G. Wermuth et al., in “The        Practice of Medicinal Chemistry”, ed. C. G. Wermuth. Academic        Press, 1996 (and the references contained therein).

The compounds of formula I may be prepared by the exemplary processesdescribed in the following reaction schemes. Exemplary reagents andprocedures for these reactions appear hereinafter and in the workingExamples.

Compounds of formula I of the invention can be prepared using thesequence of steps outlined in Schemes 1 to 5 set out below.

Scheme 1 depicts a synthesis of compounds of formula I in which R₄=anamino acid, aniline derivative or aza containing heterocyclic ring,which through their nitrogen atom is connected to the aromatic ring byan intervening (CH₂)_(n) group.

In Scheme 1, the amino acid, aniline derivative or aza containingheterocyclic ring, dissolved in a suitable solvent, is treated with 1-3molar equivalents of an appropriate base, such as potassium carbonate,cesium carbonate, potassium hydroxide or sodium hydride. The resultinganion is then alkylated with the substituted iodide 5. Othercombinations of alkylating agents or bases may be employed and are knownto those skilled in the art. The reaction mixture is stirred at roomtemperature or heated until the starting materials are consumed. Afterstandard work-up and purification, the methyl ether function is removedby treatment with 3-6 molar equivalents of a strong acid such as borontribromide at 0° C. to 25° C. in an inert solvent such asdichloromethane. The reaction mixture gives after standard work-up andpurification, the end products 6. Numerous alternative methodologies forthe conversion of intermediates such as 3 and 4 to products 6 are wellknown to those skilled in the art.

Scheme 1 also outlines the preparation of the intermediate iodide 5, thesequence similar to what is employed in: “Novel Thyroid Receptor Ligandsand Methods. Li. Yi-Lin. Liu, Ye; Hedfors, Asa; Maim, Johan; Mellin,Charlotta; Zhang, Minsheng. PCT Int. Appl., 40 pp. CODEN: PIXXD2. WO9900353 A1 990107”. An anisole-derived iodonium salt 2 and copper bronzein an inert solvent such as dichloromethane are mixed at roomtemperature. A mixture of the appropriate phenol ester 1 and a base suchas triethylamine in an inert solvent such as dichloromethane was addedto the mixture, generally using 2 molar equivalents each of the phenoland base, and 3 molar equivalents of iodonium salt 2. After stirringovernight at room temperature, the reaction mixture is purified viachromatography on silica gel, to give biaryl ether products 3. Othermethods exist in the literature for the synthesis of diaryl ethers, forexample, two references directly apply to the synthesis of thyroidhormone analogs: D. A. Evans et al., Tet. Letters, volume 39, 2937-2940(1998) and G. M. Salamonczyk et al., Tet. Letters, volume 38, 6965-6968(1997). The carboxylic acid ester can be hydrolyzed with a mixture ofaqueous sodium hydroxide and methanol. The methyl ether function can beremoved by treatment of the free acid product of the previous procedurewith 4-6 molar equivalents of a strong acid such as boron tribromide at0° C. in an inert solvent such as dichloromethane. Other combinations ofprotecting groups for the carboxylic acid present in 1 and phenolichydroxyl in iodonium salt 2 can be employed, and their usage is known tothose skilled in the art (references describing protecting groupstrategy include, for example, “Protecting Groups in Organic Chemistry”,J. F. W. McOmie, Plenum Press, London, New York, 1973, and “ProtectiveGroups in Organic Synthesis”, T. W. Greene, Wiley, New York, 1984).

The intermediate ester product 3 is reduced by treatment with anappropriate reducing agent such as diisobutyl aluminium hydride in aninert solvent such as tetrahydrofuran at 0° C. If R₂ and R₃ are alkyl,then lithium aluminum hydride may be employed without the risk ofreducing away halogen substituents at those positions. Standard work-upand purification yields the desired alcohol product 4. Other reducingagents may be employed and are known to those skilled in the art.

Intermediate 4 in Scheme 1 is finally converted to the intermediateiodide 5 by treatment of alcohol 4 with 2 molar quivalents of sodiumiodide, phosphorous pentaoxide and phosphorous acid, and heated at 120°C. for 15 minutes. Numerous other methodologies for conversion of simplehydroxyl groups to the corresponding alkyl iodides are well known tothose skilled in the art.

Scheme 2 depicts a synthesis of compounds of formula I in which R₄ is atetrazole ring. Phenylacetonitrile 7 is readily prepared from benzyliciodide 5 by standard means such as reaction with sodium cyanide in asolvent mixture such as water/ethanol. Reaction of phenylacetonitrile 7,with sodium azide and ammonium chloride in dimethylformamide at elevatedtemperatures gives tetrazole derivatives 8 (Example 1 and 2), afterstandard work-up and purification procedures. In Example 2 this step wasfollowed by a standard demethylation procedure, as above, in order toremove the protecting group.

Examples of substituted tetrazoles that can be prepared by furtherchemistry are also depicted in Scheme 2. Tetrazole derivative 8 can forinstance be treated with an appropriate base such as sodium hydrogencarbonate in acetone, followed by N-alkylation with methyl iodide toafford derivatives 9 and 10, after standard work-up and purificationprocedures. Other alkylating agents and bases may be employed and areknown to those skilled in the art.

Examples of compounds of formula I in which R₄ is an amide produced bycoupling to an amino acid are shown in Scheme 3. The followingprocedures all involve the coupling of benzoic or acetic acid derivative11 (n=0 or 1), with its phenolic hydroxyl group either protected by amethyl, left unprotected or bound to a resin, with various protectedamino acids, to afford the corresponding amides 10 of3,5-dihalo-4-(4-hydroxy-3-isopropyl-phenoxy) carboxylic acids. Thecarboxylic acids 11 are readily obtained, for example, by hydrolysis ofthe corresponding esters 3.

In one procedure, a mixture of 11 with R=Me, a coupling reagent such as3-ethyl-1-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI),and a base such as 1-hydroxybenzotriazole hydrate (HBT) indichloromethane is stirred at room temperature. The appropriateprotected amino acid and N-methylmorpholine is added. The reactionmixture yields after work-up and purification by either chromatographyor recrystallization the corresponding coupled material, which afterstandard demethylation and hydrolysis procedures, gives the desiredfinal amide products (Example 87).

Several examples of coupled products, employing different protectinggroups for the carboxylic acid group was also prepared and isolated(Examples 29, 57, 71-72, 75, 77, 80-82, 84). Alternatively, amideend-products which contain free carboxylic acid groups can bere-esterified by standard procedures by, for instance, heating them in amixture of refluxing methanol and thionyl chloride, to give thecorresponding alkyl acid ester derivatives (Example 82).

In another more fruitful modification of the same procedure as above, 11is kept unprotected (R═H) from the beginning of the sequence to give,after basic hydrolysis or treatment with a Lewis acid as BBr₃, andstandard work-up and purification procedures, other examples ofcarboxylic acid amides (Example 3-24, 25-28, 56, 73-74, 76, 78-79, 83,85-86, 203, 207-208).

An amide library can also be prepared by solid phase synthesis (Examples30-55). In this procedure a methyl ester of intermediate 11 is loaded ona resin such as a Merrifield resin by standard procedures, well known tothose skilled in the art. The resulting resin is then treated withsodium hydroxide in methanol to provide the resin-bond free carboxylicacid form of 11. Each resin pin is then filled with a solution of thecorresponding aminoacid ester, PyBOP(benzotriazole-1-yl-oxy-tris-pyrrolidino phosphoniumhexafluorophosphate). HBT, and N,N-diisopropylethylamine (Hunig's base,DIEA) and an inert solvent such as dichloromethane and is stirred atroom temperature for days. Other combinations of base and couplingreagents can be employed here with successful results. After treatmentof each of the individual pins with an appropriate base such as aqueouspotassium hydroxide and washing of the resin, the amides aredisassembled from the resin by treatment of a mixture of trifluoroaceticacid, dimethylsulfite and water.

Several other related methodologies exist for the coupling of aminoacids with aromatic, as well as non-aromatic, carboxylic acids insolution or solid phase and are known to those skilled in the art.

The amino acid product 12 can reduced by treatment with an appropriatereagent such as sodium borohydride in an polar solvent such as ethanolat room temperature. If R₂ and R₃ are alkyl, then lithium aluminumhydride may be employed without the risk of reducing the halogensubstituents at those positions. Standard work-up and purificationyields the desired alcohol product. Other reducing agents may beemployed and are known to those skilled in the art.

Scheme 4 depicts a synthesis of compounds of formula I in which R₄ is anacylsulphonamide. Similar procedures as for the coupling of amino acidsabove are employed.

In one procedure, 13 is kept unprotected (R═H), mixed with a base suchas DIEA and the appropriate sulphonamide in dichloromethane.Dimethylformamide is added to the mixture if the sulphonamide does notdissolve completely. Treatment of the mixture with a base and couplingreagent combinations such as HOBt and PyBOP, gives after heating andsubsequent mild acid treatment during work-up and purification by HPLC,the desired acylsulphonamides (Example 58-70).

In an exemplified procedure, a mixture of 13 with R=Me, a couplingreagent such as 3-ethyl-1-[3-(dimethylamino)propyl]carbodiimidehydrochloride (EDCI), and a base such as dimethylaminopyridine (DMAP)and the appropriate sulphonamide in dichloromethane is stirred at roomtemperature. The reaction mixture yields after work-up and purificationby either chromatography or recrystallization the corresponding coupledmaterial, which after standard demethylation procedures, yields yetother acylsulphonamides.

Other combinations of protecting groups and procedures can be employed.For example, applying similar chemistry as above, but withR═Si(CH₃)₂t-Bu, gives further examples of acylsulphonamides afterremoval of the protecting silyl group with ammonium fluoride (Examples88-91).

The procedures described in Scheme 5 further exemplify methods for thesynthesis of compounds of formula I. Several structurally diverseamides, primary as well as secondary, were prepared as outlined inScheme 5. Many alternative procedures for the coupling of amino acidsabove can be employed and are well known to those skilled in the art.

For example, in one procedure secondary diacetic acids amides areobtained through the treatment of 15 by dimethyliminodiacetate and EDCIin dimethylformamide or dichloromethane, followed by standard work-upprocedures and final basic hydrolysis of the ester function (Example206).

In another procedure, aromatic amides were obtained by a similarprocedure as in Example 3-24 above (Example 192-202).

A library comprising 100 diverse primary and secondary amides was alsoprepared in an automated fashion, using standard literature methods(Example 92-191).

With respect to the above reaction schemes, although the various R₁, R₂,R₃, R₄ and n moieties are specifically defined, unless otherwiseindicated, it is to be understood that R₁, R₂, R₃, and R₁ may be any ofthe groups encompassed thereby and n may be 0, 1, 2, 3 or 4.

The compounds of the invention are agonist that are preferably selectivefor the hyroid hormone receptor-beta, and as such are useful in thetreatment of obesity, hypercholesterolemia and atherosclerosis bylowering of serum LDL levels, alone or in combination with a lipidmodulating drug such as an HMG-CoA reductase inhibitor, fibrate,thiazolidinedione, or MTP inhibitor, amelioration of depression alone orin combination with an antidepressant, and stimulation of bone formationto treat osteoporosis in combination with any known bone resorptioninhibitor such as alendronate sodium. In addition, the compounds of theinvention may be useful as replacement therapy in elderly patients withhypothyroidism or subclinical hypothyroidism who are at risk ofcardiovascular complications, in the treatment of the elderly to providea sense of well-being, and in the treatment of non-toxic goiter; in themanagement of papillary or follicular thyroid cancer (alone or with T₄);in the treatment of skin disorders such as psoriasis, glaucoma,cardiovascular disease such as in the prevention or treatment ofatherosclerosis, and congestive heart failure.

The compounds of the invention may also be used to treat skin disordersor diseases involving dermal atrophy such as glucocorticoid induceddermal atrophy, including restoration of dermal atrophy induced bytopical glucocorticoids, the prevention of dermal atrophy induced bytopical glucocorticoids (such as the simultaneous treatment with topicalglucocorticoid or a pharmacological product including bothglucocorticoid and a compound of the invention), therestoration/prevention of dermal atrophy induced by systemic treatmentwith glucocorticoids, restoration/prevention of atrophy in therespiratory system induced by local treatment with glucocorticoids,UV-induced dermal atrophy, or dermal atrophy induced by aging (wrinkles,etc.), wound healing, keloids, stria, cellulite, roughened skin, actinicskin damage, lichen planus, ichtyosis, acne, psoriasis, Dernier'sdisease, eczema atopic dermatitis, chloracne, pityriasis and skinscarring.

In treating skin disorders or diseases as described above, the compoundsof the invention may be used in combination with a retinoid or a vitaminD analog.

The compounds of the invention can be administered orally orparenterally such as subcutaneously or intravenously, as well as bynasal application, rectally or sublingually to various mammalian speciesknown to be subject to such maladies, e.g., humans, cats, dogs and thelike in an effective amount within the dosage range of about 0.1 toabout 100 mg/kg, preferably about 0.2 to about 50 mg/kg and morepreferably about 0.5 to about 25 mg/kg (or from about 1 to about 2500mg, preferably from about 5 to about 2000 mg) on a regimen in single or2 to 4 divided daily doses.

The active substance can be utilized in a composition such as tablet,capsule, ointment, hydrophilic ointment, cream, lotion, solution orsuspension or in other types of carrier of materials such as transdermaldevices, iontophoretic devices, rectal suppositories, inhalant devicesand the like. The composition or carrier will contain about 5 to about500 mg per unit of dosage of a compound of formula I. They may becompounded in conventional matter with a physiologically acceptablevehicle or carrier, excipient, binder, preservative, stabilizer, flavor,etc., as called for by accepted pharmaceutical practice.

The following working Examples represent preferred embodiments of thepresent invention. Appropriate procedures for the preparation ofstarting materials can be found in: “Novel Thyroid Receptor Ligands andMethods. Li, Yi-Lin; Liu, Ye; Hedfors, Asa; Malm, Johan. Mellin,Charlotta; Zhang, Minsheng. PCT Int. Appl., 40 pp. CODEN: PIXXD2. WO9900353 A1 990107”. The ¹H NMR spectra was all consistent with theassigned structures.

EXAMPLE 1 3,5-Dimethyl-4-(4-hydroxy-3-isopropylphenoxy)benzyltetrazole

To a stirred solution of3,5-dimethyl-4-(4-hydroxy-3-isopropylphenoxy)-phenylacetonitrile (154mg) in 6.3 ml of dimethyl formamide, ammonium chloride (297 mg, 5.21mmol) and sodium azide (339 mg, 5.21 mmol) was added at reflux. After4.5 hours the reaction mixture was concentrated, treated with 6 Mhydrochloric acid and extracted several times with ethyl acetate. Thecombined organic phases were dried over magnesium sulphate, filtered andconcentrated. The residue was purified by column chromatography (silicagel, 96:4:1 chloroform/methanol/acetic acid) to give 68 mg (37%) of thetitle compound.

EXAMPLE 2 3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)benzyltetrazole

(a) To a stirred solution of3,5-dichloro-4-(4-methoxy-3-isopropylphenoxy)-phenylacetonitrile (160mg) in 3.0 ml of dimethyl formamide, ammonium chloride (500 mg) andsodium azide (600 mg) was added at reflux. After 2 hours thereaction-mixture was concentrated, treated with 6 M hydrochloric acidand extracted several times with ethyl acetate. The combined organicphases were dried over magnesium sulphate, filtered and concentrated.The residue was purified by column chromatography (silica gel, 96:4:1chloroform/methanol/acetic acid) to give 60 mg (34%) of3,5-dichloro-4-(4-methoxy-3-isopropylphenoxy)benzyltetrazole.

(b) A reaction mixture of3,5-dichloro-4-(4-methoxy-3-isopropylphenoxy)-benzyltetrazole (60 mg),BF₃.Me₂S (0.5 ml) and CH₂Cl₂ (6 ml) was stirred at room temperature overnight. The yield after purification was quantitative.

EXAMPLES 3-24

General Procedure

A mixture of 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylaceticacid (222 mg), 3-ethyl-1-[3-(dimethylamino)propyl]carbodiimidehydrochloride (EDCI), (95 mg), 1-hydroxybenzotriazole hydrate (HBT), (91mg), in dichloromethane (5 ml) was stirred under argon at roomtemperature for 2 h. In a separate flask, the appropriate amino acid,triethylamine (100 mg) and 5 ml of dichloromethane was stirred for 1 hunder N₂. The two mixtures were combined and the reaction mixturestirred at 40 C over night. When the starting carboxylic acid wasconsumed, the organic phase was removed in vacuo and the residuedissolved in methanol (20 ml) and 1N NaOH (10 ml). The reaction mixturewas stirred at 40 C for 24 h and evaporated. The residue was subjectedto semi-preparative HPLC, using gradient elution as outlined below. Theamine part “R”, and the stereochemistry of the aminoacids is indicatedin the table below.

¹HPLC retention time in minutes and gradient method. Reverse phase HPLCanalyses performed on Zorbax-C8-5u-4.6×50 mm analytical columns, flowrate 3 ml/min, detection at 220 nm, and a 10 minute gradient elution bysolvent A (10% CH₃CN+10 mmol HOOH) and B (CH₃CN+10 mmol HOOH). Gradientelution was done in the following way: 0-1 min 90% A, 1-7 min to 100% B,7-9 min 100% B and 9-10 min return to 10% A. Purification of theExamples were done using a Zorbax-C8-5u-21.5×50 mm semi-preperativecolumn, flow rate 25 ml/min, detection at 220 nm, using the samegradient as for the analytical column. ²MS result obtained on a PESciExAPI150EX using electrospray, both positive and negative ion modes.Example R Mol Formel MS m/z (M + H)¹ HPLC² 3 L-Val C22H25Br2NO5 544.06.10 4 L-Val C22H25Br2NO5 544.0 6.07 5 L-Tyr C26H25Br2NO6 608.5 5.67 6

C23H27Br2NO5 558.1 6.03 7

C27H27Br2NO5S 638.2 5.49 8 D-Leu C23H27Br2NO5 558.1 5.38 9 D-TyrC26H25Br2NO6 608.2 5.00 10 D-Trp C28H26Br2N2O5 631.3 5.38 11 L-ArgC23H28Br2N4O5 601.3 4.54 12 L-Abu C21H23Br2NO5 530.2 6.22 13

C20H21Br2NO5 516.1 4.77 14

C20H21Br2NO5 516.1 4.61 15 L-Leu C23H27Br2NO5 558.1 5.38 16

C25H23Br2NO5 578.2 5.23 17 D-Pro C22H23Br2NO5 542.2 4.92 18 L-IIeC23H27Br2NO5 558.1 5.38 19

C23H25Br2NO5 556.3 5.23 20 L-Phe C26H25Br2NO5 592.0 5.46 21 L-LysC23H28Br2N2O5 573.1 3.77 22

C23H25Br2NO5 556.0 5.30 23 L-Pro C22H23Br2NO5 542.2 4.84 24

C25H23Br2NO5 578.2 5.30

EXAMPLE 25D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]methionine

(a) A solution of3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (222 mg),3-ethyl-1-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI),(106 mg), 1-hydroxybenzotriazole hydrate (HBT), (101 mg) in dimethylformamide (5.5 ml) was stirred at room temperature for 0.5 h followed byaddition of a solution of D-methionine methyl ester hydrochloride (298mg) and triethylamine (111 mg) in dimethyl formamide (2.2 ml). Afterstirring for one hour, the mixture was partitioned between water andchloroform. The organic phase was dried, filtered and concentrated. Theresidue was subjected to column chromatography (Silica gel, gradientelution with 20% to 40% ethyl acetate in petroleum ether), to give 256mg (87%) ofD-methyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropyl-phenoxy)phenylacetyl]methionate.LC-MS (electrospray): m/z 590 (M+H).

(b)D-Methyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]-methionate(88 mg) was hydrolyzed by treatment with 1 M aqueous sodium hydroxide (1ml) in methanol (2.25 ml), to give 81 mg (94%) of the title compoundafter column chromatography (Silica gel, gradient elution withchloroform, methanol and acetic acid). LC-MS (electrospray): m/z 574(M−H).

EXAMPLE 26L-N-[3,5-Dibromo-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]methionine

(a) 3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (222mg) was coupled with D-methionine hydrochloride (298 mg) using themethod described in Example 25(a), to give 236 mg (80%) ofL-methyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropyl-phenoxy)phenylacetyl]methionateafter column chromatography. (Silica gel, gradient elution with 20% to40% ethyl acetate in petroleum ether). LC-MS (electrospray): m/z 590(M+H).

(b)D-Methyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropyl-phenoxy)phenylacetyl]-methionate(24 mg) was hydrolyzed using the method described in Example 25(b) togive 20 mg (87%) of the title compound after column chromatography(Silica gel, gradient elution with chloroform, methanol and aceticacid). LC-MS (electrospray): m/z 574 (M−H).

EXAMPLE 27D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]α-methylalanine

(a) 3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (222mg) was coupled with D-α-methylalanine hydrochloride (238 mg) using themethod described in Example 25(a), to give 269 mg (92%) ofD-t-butyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]α-methylalanineafter column chromatography (Silica gel, gradient elution with 20% to40% ethyl acetate in petroleum ether). LC-MS (electrospray): m/z 586(M+H).

(b)D-t-Butyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]α-methylalanine(88 mg) was was treated with boron tribromide (1 M in dichloromethane,2.3 ml) at 0° C. The mixture was stirred overnight at room temperaturebefore ice/water was added. The layers were separated and the waterlayer was extracted with dichloromethane. The combined organic layer wasdried, filtered and concentrated, to give 46 mg (58%) of the titlecompound after column chromatography (Silica gel, gradient elution withchloroform, methanol and acetic acid). LC-MS (electrospray): m/z 528(M−H).

EXAMPLE 28D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]aspargine

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (444 mg)was mixed with 10 ml thionyl chloride and heated at reflux for 3 h. Thereaction mixture was co-evaporated with toluene to give the crude3,5-dibromo-4-(4-hydroxy-3-isopropyl-phenoxy)phenylacetyl chloride.N,O-bis(trimethylsilyl)acetamide (670 mg) was added at 0° C., undernitrogen atmosphere, to a mixture of D-Aspargine (225 mg) and 10 mlacetonitrile. The reaction mixture was further stirred at roomtemperature and a solution of3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl chloride in 10ml acetonitrile was added. After stirring for 16 h, the reaction mixturewas poured into water and the solid filtered off. The solid wasdissolved in methanol and the organic phase removed in vacuo. Theresidue was purified by HPLC to give 76 mg (14%) ofD-N-[3.5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]aspargine.LC-MS (electrospray): m/z 557 (M−H).

EXAMPLE 29L-Methyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]alanine

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (200 mg)was coupled with L-methyl alanine hydrochloride (126 mg) using themethod described in Example 25(a), to give 140 mg (60%) of the titlecompound. LC-MS (electrospray): m/z 530 (M+1).

General Procedure for the Preparation of the Amino Acid Library by SolidPhase Synthesis (Examples 30-55) Loading of the resin with3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy benzoic acid

A mixture of methyl 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoate(7.6 g, 17.1 mmol), Merrifield resin (5 g, 1.2 mmol/g) and sodiumhydride (432 mg, 18 mmol) in 100 ml of dimethyl formamide was stirred ina 250 ml round flask at 50° C. for 40 hours. After cooling, the mixturewas filtered and the resin was washed with water (3×10 ml), dimethylformamide (3×10 ml), ethyl acetate(3×10 ml) and dichloromethane(3×10ml). The resulting resin was dried in vacuum overnight to give 8.54 g ofresin, loaded with the methyl ester.

To the resin was added methanol (100 ml) and an aqueous solution ofsodium hydroxide (100 ml, 1 M). The suspension was stirred under at 80°C. for one day, cooled to room temperature and filtered. The resin waswashed with water (3×10 ml), tetrahydrofuran (3×10 ml), ethyl acetate(3×10 ml) and dichloromethane(3×10 ml), After drying under vacuum, 5.94g of resin loaded with the title compound was obtained.

Determination of the Loading Capacity of the Resin:

The resin (100 mg) was treated with a mixture of trifluoroacetic acid,dimethyl sulphite and water (85:15:5). The mixture was stirred at roomtemperature for two days. The resin was removed by filtration and theorganic phase was collected and concentrated under vacuum. The resultingresidue was chromatographed on silica gel (methanol/chloroform/aceticacid 10:90:1). The pure fractions were pooled and concentrated affording17.5 mg (51%) of 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoicacid as white solid. The loading rate was estimated as 0.04 mmol (17,5mg) per 100 mg of loaded resin.

Coupling of 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy) benzoic acid todifferent amino acids

DIVERSOMER® 8-100 synthesizer was used for syntheses and SavantSpeedVac® system for concentration.

To each of eight PINs was added 100 (±5) mg of the loaded resin (17.5mg/100 mg; 0.04 mmol/100 mg). The resin-filled PINs were placed in theholder block. Eight vials (12 ml) were placed into the reservoir rack,equipped with a magnetic stir bar and filled with a mixture consistingof the corresponding aminoacid ester (0.4 mmol), PyBOP (104 mg, 0.2mmol), HBT (27 mg, 0.2 mmol), DIEA (52 mg, 0.4 mmol) and dichloromethane(5 ml). The holder block was assembled with the reservoir rack. Thereaction was carried out at room temperature with stirring for two days.The reservoir rack was disassembled from the holder block. Each resin inthe PINs was dispended with 2 ml each of dimethyl formamide, water,ethyl acetate and dichloromethane. The washing procedure was repeatedtwice. The resin in PINs was finally dried by pressed air-flow.

Eight new vials (12 ml) were placed into the reservoir rack and eachvial was equipped with a magnetic stir bar. The holder block wasassembled with the reservoir rack. A methanolic solution of potassiumhydroxide (5 ml, 2 M) was in 1 ml increments down through the inside ofeach PIN. The apparatus was allowed to stand in a fume hood withstirring for two days. The synthesizer was disassembled and the resinswere washed with water (4×2 ml), methanol (4×2 ml) and dichloromethane(4×2 ml). The resin in PINs was dried by pressed air-flow.

The holder block was reassembled from the reservoir rack. A 50 ml stocksolution of trifluoroacetic acid/dimethyl sulphite/water(85:15:5; v/v)was prepared. The solution (5 ml) was added to each of the eight PINs in1 ml increments. The apparatus was allowed to stand in a fume hood withstirring for 2 days. The reservoir rack and the holder block wasdisassembled. Each PIN was washed with 1 ml of the above solution. Thecontents of the 8 reservoir vials were concentrated to dryness. Eachvial was partitioned between aqueous hydrochloric acid (1 ml, 1 M) andethyl acetate (2 ml). The content of the eight reservoir vials werecarefully transferred into the eight drying cartridges (Chem eluteCE1003, VARIAN), equipped with test tubes underneath. The cartridgeswere allowed to drain by gravity, rinsed with ethyl acetate (3×1.5 ml)after 5 min and finally forced to drain under reduced pressure. Theorganic layer was collected and concentrated to give the followingproducts in the yields mentioned below.

EXAMPLE 30D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]valine

12.2 mg (57.7%)

EXAMPLE 31D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]leucine

20.1 mg (92.5%)

EXAMPLE 32 L-S-Benzyl,N-[3.5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]cysteine

14.9 mg(60%)

EXAMPLE 33D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]tyrosine

5.9 mg(24.8%)

EXAMPLE 34 L-N-δ-(2,2,5,7,8-Pentamethylchroman-6-sulfonyl),N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]arginine

10.7 mg(31%)

EXAMPLE 35L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]aminobutyricacid

15.6 mg (75,5%)

EXAMPLE 36L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]valine

19.7 mg (93%)

EXAMPLE 37L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]leucine

14.8 mg (68%)

EXAMPLE 38L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]proline

8.6 mg(41%)

EXAMPLE 39L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]cysteine

2.88 mg (13.5%)

EXAMPLE 40N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl)glycine

15.8 mg (810%)

EXAMPLE 41L-N-α-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]lysine

23.5 mg (105%)

EXAMPLE 42D-N-α-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]lysine

24.9 mg (112%)

EXAMPLE 43N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]aminoisobutyricacid

6.72 mg (32.6%)

EXAMPLE 44L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]phenylglycine

7.1 mg(31%)

EXAMPLE 45D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]phenylglycine

15.1 mg (67%)

EXAMPLE 46N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]sarcosine

6.7 mg (33.4%)

EXAMPLE 47DL-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]-α-methylphenylalanine

7.4 mg (31.4%)

EXAMPLE 48L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]isoleucine

16.1 mg (70%)

EXAMPLE 49D-N-[3,5-Dibromo-4-4-hydroxy-3-isopropylphenoxy)benzoyl]methionine

11.7 mg (52%)

EXAMPLE 50L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]methionine

13.2 mg (58.6%)

EXAMPLE 51L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]phenylalanine

9.7 mg (41.9%)

EXAMPLE 52D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]phenylalanine

12.2 mg (52.9%)

EXAMPLE 53L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]cyclohexylalanine

10.1 mg(43.7%)

EXAMPLE 54 L-N-ε-(Benzyloxycarbonyl),N-α-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)-benzoyl]lysine

10 mg (36%)

EXAMPLE 55 D-N-ε-(Benzyloxycarbonyl),N-α-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)-benzoyl]lysine

24.4 mg (88%)

EXAMPLE 56L-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]alanine

3,5-Dibromo-4-4-hydroxy-3-isopropylphenoxy)phenylacetic acid (200 mg)was coupled with L-methyl alanine hydrochloride (126 mg) using themethod described in Example 25(a) and subsequently hydrolyzed using themethod described in Example 25(b). The crude mixture was purified bysemi-preparative HPLC, to give 40 mg (21%) ofL-N-[3,5-dibromo-4-4-hydroxy-3-isopropylphenoxy)phenylacetyl]alanine.LC-MS (electrospray): m/z 516 (M+H).

EXAMPLE 57L-Dimethyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamate

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (200 mg)was coupled with L-dimethyl glutamate hydrochloride (190 mg) using themethod described in Example 25(a). The crude mixture was purified bysemi-preparative HPLC, to give 150 mg (55%) of the title compound. LC-MS(electrospray): m/z 601 (M+1).

EXAMPLE 583,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-5-hydroxy-1-naphthalenesulphon-amide

To a stirred mixture of 5-hydroxy-1-naphthalenesulphonamide (0.175 mmol)in dichloromethane (0.2 ml) was added a solution of3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoic acid (0.035 mmol),DIEA (0.175 mmol) and dichloromethane (0.2 ml), dimethyl formamide wasadded to the solution if the sulphonamide not dissolved completely indichloromethane. After 15 minutes PyBOP (0.042 mmol) and HOBt (0.001mmol) in dichloromethane (0.3 ml) was added. The reaction mixture washeated at 50° C. for 20 hours. After cooling to room temperature,dichloromethane (1 ml) and citric acid solution (5%, 1 ml) was added andstirred vigorously for 30 min. The organic phase was dried, concentratedand the residue was finally subjected to semi-preparative HPLC (Silicacolumn: 250×20 mm, ethyl acetate/n-heptane (both with 0.5% acetic acid).Gradient: first 2 min 15% ethyl acetate, then over 13 min to 100% ethylacetate, then additional 5 min 100% ethyl acetate) to give 12 mg (54%)of the title compound.

EXAMPLE 593,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy]benzoyl-4-toluenesulphonamide

3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol)was coupled with toluenesulphonamide (0.175 mmol) using the methoddescribed in Example 58. Purification on HPLC of the residue gave 14 mg(69%) of the title compound.

EXAMPLE 603,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-4-nitrobenzenesulphonamide

3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (, 0.035 mmol)was coupled with 4-nitrophenylsulfonamid (0.175 mmol) using the methoddescribed in Example 58. Purification on HPLC of the residue gave 8 mg(37%) of the title compound.

EXAMPLE 61 3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl sulfamide

3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol)was coupled with sulfamide (0.175 mmol) using the method described inExample 58. Purification on HPLC of the residue gave 13 mg (73%) of thetitle compound.

EXAMPLE 623,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-5-dimethylamino-1-naphthalene-sulphonamide

3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol)was coupled with 5-dimethylamino-1-naphthalenesulphonamide (0.175 mmol)using the method described in Example 58. Purification on HPLC of theresidue gave 8 mg (34%) of the title compound.

EXAMPLE 633,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-4-aminobenzenesulphonamide

3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol)was coupled with 4-aminobenzenesulphonamide (0.175 mmol) using themethod described in Example 58. Purification on HPLC of the residue gave7 mg (34%) of the title compound.

EXAMPLE 64 Methyl-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxybenzoyl-2-sulphonamide]benzoate

3,5-Dibromo-4-4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol) wascoupled with methyl 2-sulphonamide benzoate (0.175 mmol) using themethod described in Example 58. Purification on HPLC of the residue gave12 mg (55%) of the title compound.

EXAMPLE 653,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-2-aminobenzenesulphonamide

3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol)was coupled with 2-aminobenzenesulphonamide (0.175 mmol) using themethod described in Example 58. Purification on HPLC of the residue gave11 mg (54%) of the title compound.

EXAMPLE 663,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-2-toluenesulphonamide

3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol)was coupled with 2-toluenesulphonamide (0.175 mmol) using the methoddescribed in Example 58. Purification on HPLC of the residue gave 15 mg(74%) of the title compound.

EXAMPLE 673,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-4-(2-aminoethyl)benzenesulphonamide

3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol)was coupled with 4-(2-aminoethyl)benzenesulphonamide (0.175 mmol) usingthe method described in Example 58. Purification on HPLC of the residuegave 10 mg (47%) of the title compound.

EXAMPLE 683,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-4-(2-aminomethyl)benzenesulphonamide

3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (, 0.035 mmol)was coupled with 4-(2-aminomethyl)benzenesulphonamide (0.175 mmol) usingthe method described in Example 58. Purification on HPLC of the residuegave 16 mg (76%) of the title compound.

EXAMPLE 693,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-3-nitrobenzenesulphonamide

3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol)was coupled with 3-nitrobenzenesulphonamide (0.175 mmol) using themethod described in Example 58. Purification on HPLC of the residue gave7 mg (33%) of the title compound.

EXAMPLE 703,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-4-chlorobenzenesulphonamide

3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol)was coupled with 4-chlorobenzenesulphonamide (0.175 mmol) using themethod described in Example 58. Purification on HPLC of the residue gave13 mg (62%) of the title compound.

EXAMPLE 71L-Dimethyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamate

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (200 mg)was coupled with L-dimethyl glutamate hydrochloride (190 mg) using themethod described in Example 25(a). The crude mixture was purified bysemi-preparative HPLC, to give 150 mg (55%) of the title compound. LC-MS(electrospray): m/z 601 (M+H).

EXAMPLE 72L-(O-tert-butyl)methyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamate

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (200 mg)was coupled with L-(O-tertbuthyl)methyl glutamate hydrochloride (228 mg)using the method described in Example 25(a). The crude mixture waspurified by semi-preparative HPLC, to give 70 mg (24%) of the titlecompound. LC-MS (electrospray): m/z 643 (M+H).

EXAMPLE 73L-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamicacid

3,5-Dibromo-44-hydroxy-3-isopropylphenoxy)phenylacetic acid (200 mg) wascoupled with L-dimethyl glutamate hydrochloride (190 mg) using themethod described in Example 25(a) and subsequently hydrolyzed using themethod described in Example 25(b). The crude mixture was purified bysemi-preparative HPLC, to give 62 mg (31%) of the title compound. LC-MS(electrospray): m/Z 574 (M+H).

EXAMPLE 74L-N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]asparticacid

(a) A solution of3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (50 mg),3-ethyl-1-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI),(30 mg), 1-hydroxybenzotriazole hydrate (HBT), (28 mg) in dimethylformamide (1 ml) was stirred at room temperature for 0.5 h followed byaddition of a solution of L-di-t-butyl aspartate hydrochloride (52 mg)and triethylamine (32 mg) in dimethyl formamide (1 ml). After stirringfor three days, the mixture was partitioned between water and ethylacetate. The organic phase was washed with brine and then dried,filtered and concentrated. The residue was chromatographed on silica geleluted with ethyl acetate/light petroleum ether (1:4). Pure fractionswere pooled and concentrated to give L-di-t-butyl N-[3,5-dichloro-4(4-hydroxy-3-isopropylphenoxy)phenylacetyl]aspartate (68 mg, 83%).

(b) The above ester (48 mg) was hydrolyzed using the method described inExample 25(b) to giveL-N-[3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]asparticacid (27 mg, 70%).

EXAMPLE 75D-di-tert-butyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetylglutamate

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (200 mg)was coupled with D-di-tert-butyl glutamate hydrochloride (266 mg) usingthe method described in Example 25(a). The crude mixture was purified bysemi-preparative HPLC, to give 170 mg (70%) of the title compound. LC-MS(electrospray): m/z 685 (M+H).

EXAMPLE 76D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamicacid

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (200 mg)was coupled with D-di-tert-butyl glutamate hydrochloride (190 mg) usingthe method described in Example 25(a) and subsequently hydrolyzed usingthe method described in Example 25(b). The crude mixture was purified bysemi-preparative HPLC, to give 60 mg (23%) of the title compound. LC-MS(electrospray): m/z 574 (M+H).

EXAMPLE 77L-O-tert-Butyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamine

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (200 mg)was coupled with L-O-tert-buthyl glutamine hydrochloride (230 mg) usingthe method described in Example 25(a). The crude mixture was purified bysemi-preparative HPLC, to give 100 mg (44%) of the title compound. LC-MS(electrospray): m/z 629 (M+H).

EXAMPLE 78L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamine

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (200 mg)was coupled with L-tert-butyl glutamine hydrochloride (230 mg) using themethod described in Example 25(a) and subsequently hydrolyzed using themethod described in Example 25(b). The crude mixture was purified bysemi-preparative HPLC, to give 40 mg (15%) of the title compound. LC-MS(elctrospray): m/z 574 (M+H).

EXAMPLE 79

D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamine3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (200 mg)was coupled with D-glutamine hydrochloride (163 mg) using the methoddescribed in Example 25(a) and subsequently hydrolyzed using the methoddescribed in Example 25(b). The reaction mixture was concentrated invacuo. The residue was subjected to semi-preparative HPLC, to give 30 mg(12%) of the title compound. LC-MS (electrospray): m/z 574 (M+H).

EXAMPLE 80L-O-Benzyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]asparticacid

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (200 mg)was coupled with L-O-Benzyl aspartic acid (266 mg) using the methoddescribed in Example 25(a). The crude mixture was purified bysemi-preparative HPLC, to give 140 mg (38%) of the title compound. LC-MS(electrospray): m/z 650 (M+1).

EXAMPLE 81L-O-tert-Butyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]asparagine

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (200 mg)was coupled with L-O-tert-butyl asparagine hydrochloride (170 mg) usingthe method described in Example 25(a). The crude mixture was purified byHPLC, to give 40 mg (16%) of the title compound. LC-MS (electrospray):m/z 558 (M+H).

EXAMPLE 82L-Methyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]homoserine

3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)phenylacetic acid (134 mg)was coupled with L-homoserine (36 mg) using the method described inExample 25(a). The crude residue was dissolved in MeOH and heated atreflux with SOCl₂ for 2 h. After evaporaton of the solvent, the residuewas chromatographed on column (silica gel, CHCl₃/MeOH 97:3). Purefractions were pooled and concentrated to give 100 mg (64%) of the titlecompound.

EXAMPLE 83L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]homoserine

L-Methyl-N-[3,5-dibromo-4-4-hydroxy-3-isopropylphenoxy)phenylacetyl]-homoserine(100 mg) was hydrolyzed using the method described in Example 25(b). Thecrude product was purified by HPLC to give 30 mg (30%) ofL-N-[3,5-dibromo-4-(4-hydroxy-3-isopropyl-phenoxy)phenylacetyl]homoserine

EXAMPLE 84D-Methyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]homoserine

3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)phenylacetic acid (140 mg)was coupled with L-homoserine (36 mg) and re-esterified using the methoddescribed in Example 82. This gave 100 mg (64%) ofD-methyl-N-[3,5-dibromo-44-hydroxy-3-isopropyl-phenoxy)phenylacetyl]homoserine.

EXAMPLE 85D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]homoserine

D-Methyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]-homoserine(100 mg) was hydrolyzed using the method described in Example 25(b). Thecrude product was purified by HPLC to give 30 mg (30%) ofD-N-[3,5-dibromo-4-(4-hydroxy-3-isopropyl-phenoxy)phenylacetyl]homoserine.

EXAMPLE 86N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]glycine

(a) A stirred mixture of3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)benzoic acid (9.56 g, 28.02mmol), methyl glycine ester hydrochloride (5.28 g, 42.05 mmol),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.45 g,33.64 mmol), 1-hydroxybenzotriazole (4.54 g, 33.60 mmol), CH₂Cl₂ (260mL) and DMF (20 mL) was cooled with an ice-H₂O bath. N-methylmorpholine(5.7 g, 6.2 mL, 56.35 mmol) was added under N₂ and the reaction mixturewas allowed to attain room temperature. After 18 h, CH₂Cl₂ was removedin vacuo and the residue partionated beetween EtOAc (300 mL) and H₂O(150 mL). The organic phase was successively washed with 1N HCl (2×150mL), saturated aqueous NaHCO₃ (2×150 mL), and brine (2×150 mL). Theorganic phase was dried (Na₂SO₄), filtered and concentrated in vacuo togive 11.5 g of crude product as an orange solid. The crude product waspurified by chromatography (Silica gel, 40% EtOAc in hexane) to give9.76 g (84% yield) of slightly yellowish solid. ¹H NMR (500 MHz, CDCl₃):δ 7.82 (s, 2H), 6.78 (d, 1H, J=2.7 Hz), 6.63 (d, 1H, J=8.8 Hz), 6.61 (t,1H, J=4.9 Hz), 6.38 (dd, 1H, J=8.8, 3.3 Hz), 4.65 (s, 1H), 4.24 (d, 2H,J=S Hz), 3.82 (s, 3H), 3.16 (heptet, 1H, 6.6 Hz), 1.22 (d, 6H, J=6.6Hz); ¹³C NMR: δ 170.18, 164.65, 150.66, 148.36, 136.26, 131.63, 130.57,128.10, 115.76, 113.94, 112.28, 52.69, 41.87, 27.34,22.38;MS-ESI-[M-H]-=410, 412, 414 (100:64:10).

(b) To a solution of methylN-[3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)-benzoyl] glycinate(7.30 g, 17.71 mmol) in THF (106 mL) was added 1 N aqueous lithiumhydroxide solution (53 mL, 53 mmol). After 2 h, the mixture wasacidified with 1 N HCl and extracted with EtOAc (200 mL). The organicphase was washed with brine (2×75 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. The concentrate was triturated with CH₂Cl₂(100mL) and the white solid material obtained was dried in vacuo to give6.85 g of the title product (97% yield). ¹H NMR (500 MHz, CD₃OD): δ 7.82(s, 2H), 6.78 (d, 1H, J=2.7 Hz), 6.63 (d, 1H, J=8.8 Hz), 6.61 (t, 1H,J=4.9 Hz), 6.38 (dd, 1H, J=8.8, 3.3 Hz), 4.65 (s, 1H), 4.24 (d, 2H, J=5Hz), 3.16 (heptet, 1H, 6.6 Hz), 1.22 (d, 6H, J=6.6 Hz); ¹³C NMR: δ172.88, 167.20,151.81, 151.34, 151.13, 137.67,133.40, 131.39,129.63,116.41, 114.19, 113.28,42.27,28.19, 22.85;MS-ESI-[M−H]-=396,398,400(100:64:10).

EXAMPLE 87N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]sarcosine

(a) To a solution of3,5-dichloro-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (60 mg, 0.169mmol) in CH₂Cl₂ (10 mL) cooled with an ice-H₂O bath was added sarcosinemethyl ester hydrochloride (35.4 mg, 0.253 mmol),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (38.9 mg,0.203 mmol) and I-hydroxy-7-azabenzotriazole (27.6 mg, 0.203 mmol) andN-methylmorpholine (34.2 mg, 37 μL, 0.338 mmol). The mixture was allowedto warm up to RT and left to stir overnight (ca 18 h). The mixture wastaken up in EtOAc (50 mL) and H₂O (20 mL). The organic layer wasseparated and then it was washed successively with 1N HCl (2×25 mL),saturated NaHCO₃ aqueous solution (2×25 mL) and brine (2×25 mL). Theorganic extract was dried (Na₂SO₄), filtered and concentrated in vacuo.The crude product was purified by chromatography (25 g silica gel. 30%EtOAc in hexane) to give 41 mg of purified material (55% yield).Satisfactory proton and LC-MS were obtained.

(b) To a solution of the product above (30 mg, 0.068 mmol) in anhydrousCH₂Cl₂ (3 mL) cooled with an ice-H₂O bath was added boron tribromide(0.7 mL, 1.0 M in CH₂Cl₂, 0.7 mmol). After 2 h, the mixture was pouredinto ice-H₂O (25 mL). After 15 min of stirring, the product wasextracted with EtOAc (50 mL). The organic extract was washed with brine(2×25 mL), dried (MgSO₄), filtered and concentrated in vacuo. The crudeproduct, a mixture of free acid and methyl ester, was dissolved in THF(2 mL) and 1N lithium hydroxide aqueous solution (1 mL) was added. Afteran hour, the mixture was acidified with 1N HCl and then extracted withEtOAc (25 mL). The EtOAc extract was washed with brine (2×15 mL), dried(Na₂SO₄), filtered and concentrated in vacuo to give 35 mg of crudeproduct. The crude product was purified by prep HPLC to give 12.3 mg ofslightly yellowish solid as purified material (44% yield). Satisfactoryproton and mass spectra were obtained.

EXAMPLE 883,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl-5-dimethylamino-1-naphthalenesulphonamide

To a solution of the3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (50 mg,0.09 mmol), dimethylaminopyridine (4 mg, 0.018 mmol) and5-dimethylamino-1-naphthalenesulphonamide (45 mg, 0.18 mmol) in 50%dichloromethane in dimethyl formamide (0.2 ml) was added a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28 mg, 0.13mmol) and diisopropylethyl amine (17 mg, 0.13 mmol) in 50% methylenechloride in dimethyl formamide (0.2 ml). The reaction mixture wasvortexed and allowed to stand at room temperature for 6 hours. Asolution of ammonium fluoride (0.5 M in methanol; 0.4 ml) was added.After 16 hours, the reaction mixture was evaporated to dryness,re-dissolved in a solvent mixture containing 90% methanol, 10% water and0.1% trifluoroacetic acid (2 ml) and purified by preparative HPLC (YMCS5 ODS 30×250 mm: 50-100% solvent B in 30 min: solvent A-90% water, 10%methanol, 0.1% trifluoroacetic acid; solvent B-10% water, 90% methanol,0.1% trifluoroacetic acid: flow rate 25 ml per min: detection 220 nm).The yield was 10.1 mg (16%).

EXAMPLE 89-91

These compounds were prepared and purified in a similar manner as above.For a table of Examples 88-91 comprising the coupled sulphonamide,retention times and mass spectra, see Scheme below.

Example R MS (ESI+) R_(t) (min)¹ 88

677 6.9 89

598 4.3 90

722 5.1 91

648 4.9

¹YMC ODS 4.6×50 mm: 50-100% solvent B in 8 min: solvent A-90% water, 10%methanol, 0.2% phosphoric acid; solvent B-10% water, 90% methanol, 0.2%phosphoric acid: flow rate 2.5 ml per min: detection 220 nm

EXAMPLES 92-191

Procedures for the synthesis of the library compounds indicated in theTable below are described in Lawrence, R. M.; Biller, S. A.; Fryszman,O. M.; Poss, M. A. Synthesis 1997, 553.

¹HPLC retention time in minutes and gradient method. Reverse phase HPLCanalyses performed on YMC S5 ODS 4.6×50 mm analytical columns, detectionat 220 nm, and 4 minute gradient elutions by either: method a, 0% B,100% A to 100% B, 0% A; or method b, 20% B, 80% A to 100% B, 0% A, wheresolvent A is 90% water, 10% methanol, 0.2% phosphoric acid and solvent Bis 10% water, 90% methanol, 0.2% phosphoric acid.

²MS result obtained on a Micromass Platform II using electrospray, bothpositive and negative ion modes.

³Method A examples were prepared by synthesis procedure A in thereference cited above. In these examples, a second basic nitrogen ispresent in the amine coupling partner. However, only one nitrogen iscapable of giving the normal acylation product. Method B examples wereprepared by procedure C in the reference cited above. Example -NR′R″HPLC¹ MS² Formula Method³ 92 3-(AMINOMETHYL)PYRIDINE 2.76, a m/z 534.84(M + H) C23H22Br2N2O3 A 93 2-(2-AMINOETHYL)PYRIDINE 2.73, a m/z 548.83(M + H) C24H24Br2N2O3 A 94 3-(2-AMINOETHYL)PYRIDINE 2.73, a m/z 548.82(M + H) C24H24Br2N2O3 A 95 2-(AMINOMETHYL)PYRIDINE 2.84, a m/z 534.85(M + H) C24H30Br2N2O3 A 96 4-(AMINOMETHYL)PYRIDINE 2.74, a m/z 534.82(M + H) C24H30Br2N2O3 A 97 1-(4-METHOXYPHENYL)PIPERAZINE 3.33, a m/z618.81 (M + H) C29H32Br2N2O3 A DIHYDROCHLORIDE 981-(2-FLUOROPHENYL)PIPERAZINE 3.53, a m/z 607.16 (M + H) C34H32Br2N2O3 A99 2-(2-(AMINOMETHYL) 4.42, a m/z 671.97 (M + H) C31H29Br2NO4S BPHENYLTHIO)BENZYL ALCOHOL 100 2-(1-CYCLOHEXENYL)ETHYLAMINE 4.56, a m/z551.98 (M + H) C25H29Br2NO3 B 101 2-AMINOINDAN 4.44, a m/z 559.88 (M +H) C26H25Br2NO3 B 102 2-AMINOMETHYLBENZODIOXAN 4.39, a m/z 591.93 (M +H) C26H25Br2NO5 B 103 3-PHENYL-1-PROPYLAMINE 4.44, a m/z 560.00 (M − H)C26H27Br2NO3 B 104 2-(P-TOLYL)ETHYLAMINE 4.48, a m/z 559.95 (M − H)C26H27Br2NO3 B 105 1-(3-AMINOPROPYL)-2-PYRROLIDINONE 3.97, a m/z 568.97(M + H) C24H28Br2N2O4 B 106 BETA-ALANINE 4.52, a m/z 670.88 (M + H)C31H30Br2N2O5 B 4-METHOXY-BETA-NAPHTHYLAMIDE 107 2-CHLOROBENZYLAMINE4.38, a m/z 612.98 (M + ?) C24H22Br2ClNO3 B 108 2-AMINOMETHYL-3- 4.65, am/z 660.08 (M + H) C30H26Br2ClNO4 B CHLORODIPHENYLETHER 109DL-ALPHA-AMINO-EPSILON- 4.03, a m/z 554.86 (M + H) C23H26Br2N2O4 BCAPROLACTAM 110 L-PHENYLALANINOL 4.22, a m/z 577.92 (M + H) C26H27Br2NO4B 111 4-(1,2,3-THIADIAZOL-4-YL) 4.21, a m/z 617.69 (M + H)C26H23Br2N3O3S B BENZYLAMINE 112 2-AMINOMETHYLTHIOPHENE 4.21, a m/z539.84 (M + H) C22H21Br2NO3S B 113 1-(1-NAPHTHYL)ETHYLAMINE 4.54, a m/z597.83 (M + H) C29H27Br2NO3 B 114 3-CHLORO-4-METHYLBENZYLAMINE 4.53, am/z 581.80 (M + H) C25H24Br2ClNO3 B 115 TETRAHYDROFURFURYLAMINE 4.07, am/z 527.90 (M + H) C22H25Br2NO4 B 116 2,4-DICHLOROPHENETHYLAMINE 4.66, am/z 615.73 (M + H) C25H23Br2Cl2NO3 B 117 ETHYL 4.21, a m/z 599.05 (M +H) C25H30Br2N2O5 B 4-AMINO-1-PIPERIDINECARBOXYLATE 1182,6-DIFLUOROBENZYLAMINE 4.25, a m/z 569.82 (M + H) C24H21Br2F2NO3 B 1192-IODOBENZYLAMINE 4.46, a m/z 659.45 (M + H) C24H22Br2INO3 B 1202-METHYLBENZYLAMINE 4.38, a m/z 547.89 (M + H) C25H25Br2NO3 B 121BENZYLAMINE 4.27, a m/z 533.85 (M + H) C24H23Br2NO3 B 1223-METHYLBENZYLAMINE 4.38, a m/z 547.89 (M + H) C25H25Br2NO3 B 1232-METHOXYPHENETHYLAMINE 4.41, a m/z 577.81 (M + H) C26H27Br2NO4 B 1243-METHOXYPHENETHYLAMINE 4.35, a m/z 577.87 (M + H) C26H27Br2NO4 B 1252-ETHOXYBENZYLAMINE 4.42, a m/z 577.86 (M + H) C26H27Br2NO4 B 126(R)-(−)-1-CYCLO-HEXYLETHYLAMINE 4.56, a m/z 553.90 (M + H) C25H31Br2NO3B 127 4-METHOXYPHENETHYLAMINE 4.32, a m/z 577.83 (M + H) C26H27Br2NO4 B128 2-FLUOROBENZYLAMINE 4.27, a m/z 551.85 (M + H) C24H22Br2FNO3 B 1292-CHLORO-6-METHYLBENZYLAMINE 4.48, a m/z 581.85 (M + H) C25H24Br2ClNO3 B130 4-CHLOROBENZYLAMINE 4.42, a m/z 567.83 (M + H) C24H22Br2ClNO3 B 131BETA-METHYLPHENETHYLAMINE 4.43, a m/z 561.88 (M + H) C26H27Br2NO3 B 1321,1-DI(P-ANISYL)METHYLAMINE 4.47, a m/z 669.88 (M + H) C32H31Br2NO5 B133 MAYBRIDGE BTB 12133 4.18, a m/z 623.84 (M + H) C27H29Br2NO6 B 134DL-2-AMINO-1-PENTANOL 4.12, a m/z 529.91 (M + H) C22H27Br2NO4 B 135L-PHENYLALANINE 4.56, a m/z 711.88 (M + H) C32H29Br2N3O6 BP-NITROANILIDE 136 ETHYL 3-AMINOBUTYRATE 4.16, a m/z 557.85 (M + H)C23H27Br2NO5 B 137 (1S,2R)-(+)-2-AMINO- 4.28, a m/z 639.92 (M + H)C31H29Br2NO4 B 1,2-DIPHENYLETHANOL 138 2-FLUOROPHENETHYLAMINE 4.37, am/z 565.90 (M + H) C25H24Br2FNO3 B 139 2-ETHYLHEXYLAMINE 4.70, a m/z555.93 (M + H) C25H33Br2NO3 B 140 3-FLUOROPHENETHYLAMINE 4.36, a m/z565.85 (M + H) C25H24Br2FNO3 B 141 (1S,2S)-(+)-2-AMINO-3- 4.19, a m/z607.89 (M + H) C27H29Br2NO5 B METHOXY-1-PHENYL-1-PROPANOL 142 NONYLAMINE4.88, a m/z 569.95 (M + H) C26H35Br2NO3 B 143 2,5-DICHLOROBENZYLAMINE4.49, a m/z 601.72 (M + H) C24H21Br2Cl2NO3 B 144 2-METHYLCYCLOHEXYLAMINE4.44, a m/z 539.91 (M + H) C24H29Br2NO3 B 145 3-METHYLCYCLOHEXYLAMINE4.51, a m/z 539.90 (M + H) C24H29Br2NO3 B 146 3-N-PROPOXYPROPYLAMINE4.30, a m/z 543.90 (M + H) C23H29Br2NO4 B 147 2,3-DIMETHYLBENZYLAMINE4.48, a m/z 561.91 (M + H) C26H27Br2NO3 B 148 3-CHLOROBENZYLAMINE 4.40,a m/z 567.79 (M + H) C24H22Br2ClNO3 B 149 4-TERT-BUTYLCYCLOHEXYLAMINE4.80, a m/z 581.97 (M + H) C27H35Br2NO3 B 150 (1S,2S)-(+)-THIOMICAMINE3.94, a m/z 639.80 (M + H) C27H29Br2NO5S B 151 2,4-DIMETHYLBENZYLAMINE4.49, a m/z 561.89 (M + H) C26H27Br2NO3 B 152 2-AMINOETHYL PHENYL 4.44,a m/z 579.83 (M + H) C25H25Br2NO3S B SULFIDE 153 PHENETHYLAMINE 4.36, am/z 547.87 (M + H) C25H25Br2NO3 B 154 TYRAMINE 4.04, a m/z 563.86 (M +H) C25H25Br2NO4 B 155 L-TYROSINE METHYLESTER 4.01, a m/z 621.97 (M + H)C27H27Br2NO6 B 156 BENZHYDRYLAMINE 4.52, a m/z 609.82 (M + H)C3OH27Br2NO3 B 157 4-METHOXYBENZYLAMINE 4.25, a m/z 563.85 (M + H)C25H25Br2NO4 B 158 2,3-DICHLOROBENZYLAMINE 4.52, a m/z 601.71 (M + H)C24H21Br2Cl2NO3 B 159 GLYCINE N-BUTYL ESTER 4.03, b m/z 557.85 (M + H)C23H27Br2NO5 B HYDROCHLORIDE 160 D-(−)-ALPHA-PHENYLGLYCINE 4.11, b m/z605.84 (M + H) C27H27Br2NO5 B ETHYL ESTER HYDROCHLORIDE 1614-CHLORO-2-FLUOROBENZYLAMINE 4.27, b m/z 585.80 (M + H) C24H21Br2ClFNO3B HYDROCHLORIDE 162 TRANS-2-PHENYLCYCLOPROPYLAMINE 4.22, b m/z 559.86(M + H) C26H25Br2NO3 B HYDROCHLORIDE 163 ETHYL 4-AMINOBUTYRATE 3.87, bm/z 557.85 (M + H) C23H27Br2NO5 B HYDROCHLORIDE 164 DL-HOMOCYSTEINETHIOLACTONE 3.65, b m/z 543.80 (M + H) C21H21Br2NO4S B HYDROCHLORIDE 1654-NITROBENZYLAMINE 3.99, b m/z 578.85 (M + H) C24H22Br2N2O5 BHYDROCHLORIDE 166 NORPHENYLEPHRINE 3.60, b m/z 579.84 (M + H)C25H25Br2NO5 B HYDROCHLORIDE 167 GLYCINE ETHYL ESTER 3.71, b m/z 529.87(M + H) C21H23Br2NO5 B HYDROCHLORIDE 168 DL-ALANINE ETHYL ESTER 3.83, bm/z 543.86 (M + H) C22H25Br2NO5 B HYDROCHLORIDE 169 SARCOSINE ETHYLESTER 3.79, b m/z 543.92 (M + H) C22H25Br2NO5 B HYDROCHLORIDE 1704-NITRO-N-PROPYLBENZYLAMINE 4.29, b m/z 620.89 (M + H) C27H28Br2N2O5 BHYDROCHLORIDE 171 PIPERIDINE 3.98, b m/z 511.93 (M + H) C22H25Br2NO3 B172 3-METHYLPIPERIDINE 4.14, b m/z 525.91 (M + H) C23H27Br2NO3 B 1733-(HYDROXYMETHYL)-PIPERIDINE 3.66, b m/z 541.89 (M + H) C23H27Br2NO4 B174 1,2,3,4-TETRAHYDROISOQUINOLINE 4.23, b m/z 559.85 (M + H)C26H25Br2NO3 B 175 2-ETHYLPIPERIDINE 4.25, b m/z 539.90 (M + H)C24H29Br2NO3 B 176 3,4-DICHLORO-N-ETHYLBENZYLAMINE 4.54, b m/z 629.75(M + H) C26H25Br2Cl2NO3 B 177 2-METHYLPYRROLIDINE 3.99, b m/z 511.90(M + H) C22H25Br2NO3 B 178 N-ETHYL-N-PROPYLAMINE 4.11, b m/z 513.89 (M +H) C22H27Br2NO3 B 179 4-METHYLPIPERIDINE 4.15, b m/z 525.91 (M + H)C23H27Br2NO3 B 180 (S)-(+)-2-(METHOXYMETHYL) 3.99, b m/z 541.90 (M + H)C23H27Br2NO4 B PYRROLIDINE 181 N-BENZYLETHANOLAMINE 4.01, b m/Z 577.86(M + H) C26H27Br2NO4 B 182 DIBENZYLAMINE 4.56, b m/z 623.79 (M + H)C31H29Br2NO3 B 183 4-BENZYL-4-HYDROXYPIPERIDINE 4.12, b m/z 617.88 (M +H) C29H31Br2NO4 B 184 (R)(−)-2-BENZYLAMINO-1- 4.16, b m/z 605.83 (M + H)C28H31Br2NO4 B BUTANOL 185 N-(N-ETHYLAMINOACETYL)- 4.00, b m/z 632.69(M + H) C29H32Br2N2O4 B 2,6-DIMETHYLANILINE 186N-ETHYL-O-METHOXYBENZYLAMINE 4.35. b m/z 591.93 (M + H) C27H29Br2NO4 B187 MAYBRIDGE NRB 01961 4.40, b m/z 647.88 (M + H) C30H33Br2NO5 B 1882-((N-ETHYLAMINO)METHYL)- 4.05, b m/z 622.80 (M + H) C26H26Br2N2O6 B4-NITROPHENOL 189 MAYBRIDGE SEW 01484 4.48, b m/z 671.89 (M + H)C31H29Br2NO4S B 190 3-AZABICYCLO-[3.2.2]NONANE 4.28, b m/z 551.89 (M +H) C25H29Br2NO3 B 191 N-(2-METHOXY-ETHYL)ETHYLAMINE 3.89, b m/z 529.88(M + H) C22H27Br2NO4 B

General Procedure

3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)benzoic acid was coupledwith the appropriate amino acid, using the general procedure outlinedfor Examples 3-24. The residue was subjected to semi-preparative HPLC,using the same gradient elution as outlined for Examples 3-24. The aminepart “R” and the stereochemistry of the aminoacids is indicated in thetable below. Retention times, yields and the mass of the individualproducts are also given below. Example R Yield % MS m/z (M + H)¹ HPLC192

64 407.3 7.3 193

61 426.1 7.1 194

59 435.2 6.6 195

40 440.1 6.7 196

88 452.3 6.6 197

76 452.2 6.7 198

71 453.2 6.5 199

39 460.1 7.6 200

55 467.9 6.7 201

31 506.3 7.5 202

72 514.4 7.0 203

52 473.2 8.0

EXAMPLE 2042-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzyl]-4-thiazole aceticacid

(a) A reaction mixture of3,5-dibromo-44-methoxy-3-isopropylphenoxy)phenyl acetamide (150 mg) andLawesson's reagent (100 mg) in dioxane (3 mL) was stirred at roomtemperature for 15 hours. The resulting suspension as filtered andpoured onto ice-water and stirred. The water phase was extracted withEtOAc (3×7 mL) and the combined organic phases were washed with water.The organic phase was dried over Na₂SO₄, concentrated and gave 153 mg ofcrude 3,5-dibromo-4-(4-methoxy-3-isopropylphenoxy)phenyl thioamide. Thecrude product was used directly in the next step.

(b) To a suspension of 3,5-dibromo-4-4-methoxy-3-isopropylphenoxy)phenylthioamide (80 mg) in EtOH (2 mL), ethylchloroacetoacetonate (0.03 mL)was added. The mixture was stirred in a closed tube at 75 C for 2 h. Thereaction mixture was concentrated and EtOAc and water was added. Thewater phase was extracted with EtOAc (3×5 in L) and the combined organicphases were washed with NaHCO₃ (sat. solution). The organic phase wasdried over Na₂SO₄, concentrated and purified by chromatography (silicagel, 15% EtOAc/p-ether). This gave 80 mg (86%) ofethyl-2-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzyl]-4-thiazoleacetate.

(c) BF₃.Et₂ (0.06 mL) was added slowly to a solution of the ethyl ester(60 mg) in CH₂Cl₂ (4 mL). The reaction mixture was stirred at roomtemperature for 2 days. Water was added. The water phase was extractedwith EtOAc (3×5 mL) and the combined organic phases were washed with anaqueous solution of HCl (1N). The organic phase was dried over Na₂SO₄,concentrated and purified by semi-preparative HPLC. This gave 20 mg(37%) of the title compound.

EXAMPLE 2052-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzyl]-4-methylthiazole

(a) 3,5-dibromo-4-(4-methoxy-3-isopropylphenoxy)phenyl thioamide (70 mg)in EtOH (2 mL) was reacted with ethylchloroacetoacetonate (0.014 mL)using the method described in Example 204(b). The crude product waspurified by chromatography (silica gel, 15% EtOAc/p-ether). This gave 60mg (78%) of2-[3,5-dibromo-4-(4-methoxy-3-isopropylphenoxy)benzyl]4-methylthiazole.

(b) The above methoxy compound (50 mg) was demethylated with BF₃.Et₂(0.06 mL), using the method described above. The crude mixture waspurified by semi-preparative HPLC. This gave 20 mg (41%) of the titlecompound.

EXAMPLE 2063,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)phenylformylimino diaceticacid

(a) To a solution of3,5-dichloro-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (60 mg, 0.169nmol) in CH₂Cl₂ (10 mL) cooled with an ice-H₂O bath was addeddiethyliminodiacetate (35.4 mg, 0.253 mmol),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (38.9 mg,0.203 mmol) and 1-hydroxy-7-azabenzotriazole (27.6 mg, 0.203 mmol). Themixture was allowed to warn up to room temperature and left to stirovernight (ca. 18 h). The mixture was taken up in EtOAc (50 mL) and H₂O(20 mL). The organic layer was separated and then it was washedsuccessively with 1N HCl (2×25 mL), saturated NaHCO₃ aqueous solution(2×25 mL) and brine (2×25 mL). The organic extract was dried (Na₂SO₄),filtered and concentrated in vacuo. The crude product was purified bychromatography (25 g silica gel, 15% EtOAc in hexane) to give 31 mg ofpurified material (35% yield). Satisfactory proton and LC-MS wereobtained.

(b) To a solution of above ethyl ester (25 mg, 0.047 mmol) in anhydrousCH₂Cl₂ (3 mL) cooled with an ice-H₂O bath was added boron tribromide(0.7 mL, 1.0 M in CH₂Cl₂, 0.7 mmol). After 2 h, the mixture was pouredinto ice-H₂O (25 mL). After 15 min of stirring, the product wasextracted with EtOAc (50 mL). The organic extract was washed with brine(2×25 mL), dried (MgSO₄), filtered and concentrated in vacuo. The crudeproduct, a mixture of free acid and methyl ester, was dissolved in THF(2 mL) and 1N lithium hydroxide aqueous solution (1 mL) was added. Afteran hour, the mixture was acidified with 1N HCl and then extracted withEtOAc (25 mL). The EtOAc extract was washed with brine (2×15 mL), dried(Na₂SO₄), filtered and concentrated in vacuo to give 27.7 mg of crudeproduct. The crude product was purified by prep HPLC to give 9.2 mg(38%) of of the title compound as a slightly yellow solid. Satisfactoryproton and mass spectra were obtained.

EXAMPLE 207N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]-beta-alanine

(a) 3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoic acid (50 mg,0.116 mmol), beta-alanine methyl ester hydrochloride (70 mg, 0.42 mmol),and hydroxy-benzotriazole (78 mg, 0.57 mmol) were dissolved indichloromethane (0.6 mL), N,N-dimethylformamide (0.2 mL) and triethylamine (0.12 mL, 0.58 mmol). The solution was cooled to 0 C and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrogen chloride (110 mg,0.58 mmol) was added. The reaction was warmed to room temperature andstirred for 12 hours. The reaction was diluted with dichloromethane (100mL) and washed with water (2×150 mL). The organic layer was washed oncewith brine (100 ml), dried over sodium sulfate and concentrated invacuo. The methyl ester (50 mg, 90% yield) was purified bychromathography (silica gel, 7:3 hexane/ethyl acetate).

(b) The crude ester was dissolved in 1.0 mL of methanol and 0.4 mL of 1N sodium hydroxide. The hydrolysis was complete in 2 hours. The methanolwas removed and the aqueous layer was acidified with aqueoushydrochloric acid (1 N). The aqueous layer was extracted with ethylacetate (3×100 mL). The combined organic layers were washed with brine(2×75 mL) and dried over sodium sulfate. The organic layer wasconcentrated in vacuo. The title compound (51 mg, 98%) was obtainedwithout further purification. Satisfactory ¹H-NMR, ¹³C-NMR and massspectra was obtained for the title compound.

EXAMPLE 208N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]-beta-alanine

(a) The ester was prepared by adding the reagents to the reaction in themanner described in Example 207. The starting acid (122 mg, 0.356 mmol),B-alanine methyl ester hydrochloride, and hydroxybenzotriazole (240 mg,1.76 mmol) were dissolved in triethyl amine (0.6 mL, 2.5 mmol),dichloromethane 1.2 mL, and 0.8 mL of dimethylamide.The1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrogen chloride (110mg, 0.58 mmol) was added in the manner as described above. The ester (75mg, 50%) was isolated without further purification.

(b) The ester was dissolved in 3.0 mL of methanol and 1.6 mL of 1 Nsodium hydroxide using the procedure described for title acid. The titleacid (72 mg, 98% yield) was obtained from the reaction. The acid wasfurther purified by preparative HPLC using a YMC ODS 20×100 mm columnwhich yielded 53.6 mg (74% yield) of the purified acid.

EXAMPLE 209L-N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]serine

3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)benzoic acid (122 mg) wascoupled with L-serin methyl ester hydrochloride using the methoddescribed in Example 207(a) and subsequently hydrolyzed using the methoddescribed in Example 207(b). The crude mixture was purified as above.Satisfactory ¹H-NMR, ¹³C-NMR and mass spectra was obtained for the titlecompound.

EXAMPLE 210D-N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]serine

3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)benzoic acid (122 mg) wascoupled with D-serin methyl ester hydrochloride using the methoddescribed in Example 207(a) and subsequently hydrolyzed using the methoddescribed in Example 207(b). The crude mixture was purified as above.Satisfactory ¹H-NMR, ¹³C-NMR and mass spectra was obtained for the titlecompound.

EXAMPLES 211-228

The compounds indicated in the table below are all examples of furthercompounds, that can readily be prepared via the synthetic proceduredescribed in Example 86.

Example R₁ R₂ R₃ 211 Isopropyl Me Me 212 Isopropyl Me Br 213 IsopropylMe CI 214 Isopropyl Me I 215 Isopropyl I I 216 Isopropyl I Cl 217Isopropyl I Br 218 Isopropyl Br Cl 219 I Me Me 220 I Me Br 221 I Me Cl222 I Me I 223 I I I 224 I Br Cl 225 I Br Br 226 I Cl Cl 227 I I Br 228I I Cl

EXAMPLES 229-231

-   N-[3,5-Dichloro-4-(4-hydroxy-3-bromophenoxy)benzoyl]glycine-   N-[3,5-Dichloro-4-(4-hydroxy-3-methylphenoxy)benzoyl]glycine-   N-[3,5-Dichloro-4-(4-hydroxy-3-ethylphenoxy)benzoyl]glycine

These compounds were all prepared by a method analogous to that used inExample 86. Satisfactory ¹H-NMR, ¹³C-NMR and mass spectra were obtainedfor all three compounds.

1. A compound having the formula

wherein n is an integer from 0 to 4; R₁ is halogen, trifluoromethyl, oralkyl of 1 to 6 carbons or cycloalkyl of 3 to 7 carbons; R₂ and R₃ arethe same or different and are hydrogen, halogen, alkyl of 1 to 4carbons, at least one of R₂ and R₃ being other than hydrogen, R₄ is aheteroaromatic moiety which may be substituted or unsubstituted and islinked to (CH₂), via a nitrogen atom or a carbon atom; an amine (NR′R″),including those in which the amine is derived from an alpha amino acidof either natural (L) or unnatural (D) stereochemistry; anacylsulphonamide (CONHSO₂R′); or a carboxylic acid amide (CONR′R″) withthe proviso that when n equals zero (n=0), then R₄ can only be acarboxylic acid amide or an acylsulphonamide; R₅ is hydrogen or an acyl(such as acetyl or benzoyl) or other group capable of bioconversion togenerate the free phenol structure (wherein R₅═H); including allstereoisomers thereof, prodrug esters thereof, and pharmaceuticallyacceptable salts thereof.
 2. A compound as defined in claim 1 where R₄is a carboxylic acid amide (CONR′R″) in which the amine portion of thecarboxylic amide can be derived from an achiral or a L or D alpha aminoacid such as when the general structure —CONR′R″ can be represented by

and R′, R″, R′″ and R″′ are the same or different and are independentlyselected from hydrogen, alkyl, aryl and heteroaryl, substituted orunsubstituted, and R* may be hydrogen, alky, aryl and heteroaryl,substituted or unsubstituted, and may also be any of the side chainsfound in the naturally occuring alpha-amino acids
 3. The compound asdefined in claim 2 where R′ and R* are connected to form a 4 to8-membered ring.
 4. The compound as defined in claim 2 where R′ and R*comprise consecutive —(CH₂)— groups to form proline or homoproline. 5.The compound as defined in claim 1 where n is 0 or 1 or
 2. 6. Thecompound as defined in claim 1 wherein R₂ and R₃ are each independentlyhalogen.
 7. The compound as defined in claim 1 wherein R₂ and R₃ areeach independently an alkyl group.
 8. The compound as defined in claim 1wherein one of R₂ and R₃ is halogen and the other is an alkyl group. 9.The compound as defined in claim 1 wherein one of R₂ and R₃ is halogenand the other is hydrogen.
 10. The compound as defined in claim 1wherein one of R₂ and R₃ is alkyl and the other is hydrogen.
 11. Thecompound as defined in claim 1 wherein R₂ and R₃ are independently Cl,Br, methyl or ethyl.
 12. The compound as defined in claim 1 wherein R₁is isopropyl.
 13. The compound as defined in claim 1 wherein R₄ isheteroaromatic hydrocarbon, carboxylic acid amide, or anacylsulphonamide.
 14. The compound as defined in claim 1 wherein R₅ ishydrogen.
 15. The compound as defined in claim 1 which is3,5-Dimethyl-4-(4-hydroxy-3-isopropylphenoxy)benzyltetrazole,3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)benzyltetrazole,2-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzyl]-4-thiazole aceticacid,2-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzyl]-4-methylthiazole,16. The compound as defined in claim 1 which is3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-5-hydroxy-1-naphthalenesulphon-amide,3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-4-toluenesulphonamide,3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-4-nitrobenzenesulphonamide,3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl sulfamide,3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-5-dimethylamino-1-naphthalenesulphonamide,3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-4-aminobenzenesulphonamide,Methyl-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-2-sulphonamide]benzoate,3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-2-aminobenzenesulphonamide,3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-2-toluenesulphonamide,3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-4-(2-aminoethyl)benzenesulphonamide,3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-(2-aminomethyl)benzenesulphonamide,3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-3-nitrobenzenesulphonamide,3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-4-chlorobenzenesulphonamide,and the compounds shown below,


17. The compound as defined in claim 1 which is in the table below,

and the compounds indicated in the table below,

—NR′R″ Formula 3-(AMINOMETHYL)PYRIDINE C23H22Br2N2O3 2-2-AMINOETHYLPYRIDINE C24H24Br2N2O3 3-(2-AMINOETHYL)PYRIDINE C24H24Br2N2O32-(AMINOMETHYL)PYRIDINE C24H3OBr2N2O3 4-(AMINOMETHYL)PYRIDlNEC24H3OBr2N2O3 1-(4-METHOXYPHENYL)PIPERAZINE DIHYDROCHLORIDEC29H32Br2N2O3 1-(2-FLUOROPHENYL)PIPERAZINE C34H32Br2N2O32-(2-(AMINOMETHYL)PHENYLTHIO)BENZYL ALCOHOL C31H29Br2NO4S2-(1-CYCLOHEXENYL)ETHYLAMINE C25H28Br2NO3 2-AMINOINDAN C26H25Br2NO32-AMINOMETHYLBENZODIOXAN C26H25Br2NO5 3-PHENYL-1-PROPYLAMINEC26H27Br2NO3 2-(P-TOLYL)ETHYLAMINE C26H27Br2NO31-(3-AMINOPROPYL)-2-PYRROLIDINONE C24H28BrN2O4 BETA-ALANINE4-METHOXY-BETA-NAPHTHYLAMIDE C31H30Br2N2O5 2-CHLOROBENZYLAMINEC24H22Br2ClNO3 2-AMINOMETHYL-3-CHLORODIPHENYLETHER C30H26Br2ClNO4DL-ALPHA-AMINO-EPSILON-CAPROLACTAM C23H26Br2N2O4 L-PHENYLALANINOLC26H27Br2NO4 4-(1,2,3-THIADIAZOL-4-YL)BENZYLAMINE C26H23Br2N3O3S2-AMINOMETHYLTHIOPHENE C22H21Br2NO3S 1-(1-NAPHTHYL)ETHYLAMINEC29H27Br2NO3 3-CHLORO-4-METHYL BENZYLAMINE C25H24Br2ClNO3TETRAHYDROFURFURYLAMINE C22H25Br2NO4 2,4-DICHLOROPHENETHYLAMINEC25H23Br2Cl2NO3 ETHYL 4-AMINO-1-PIPERIDINECARBOXYLATE C25H30Br2N2O52,6-DIFLUOROBENZYLAMINE C24H21Br2F2NO3 2-IODOBENZYLAMINE C24H22Br2INO32-METHYLBENZYLAMINE C25H25Br2NO3 BENZYLAMINE C24H23Br2NO33-METHYLBENZYLAMINE C25H25Br2NO3 2-METHOXYPHENETHYLAMINE C26H27Br2NO43-METHOXYPHENETHYLAMINE C26H27Br2NO4 2-ETHOXYBENZYLAMINE C26H27Br2NO4(R)-(-)-1-CYCLO-HEXYLETHYLAMINE C25H31Br2NO3 4-METHOXYPHENETHYLAMINEC26H27Br2NO4 2-FLUOROBENZYLAMINE C24H22Br2FNO32-CHLORO-6-METHYLBENZYLAMINE C25H24Br2ClNO3 4-CHLOROBENZYLAMINEC24H22Br2ClNO3 BETA-METHYLPHENETHYLAMINE C26H27Br2NO31,1-DI(P-ANISYL)METHYLAMINE C32H31Br2NO5 MAYBRIDGE BTB 12133C27H29Br2NO6 DL-2-AMINO-1-PENTANOL C22H27Br2NO4 L-PHENYLALANINEP-NITROANILIDE C32H29Br2N3O6 ETHYL 3-AMINOBUTYRATE C23H27Br2NO5(1S,2R)-(+)-2-AMINO-1,2-DIPHENYLETHANOL C31H29Br2NO42-FLUOROPHENETHYLAMINE C25H24Br2FNO3 2-ETHYLHEXYLAMINE C25H33Br2NO33-FLUOROPHENETHYLAMINE C25H24Br2FNO3(1S,2S)-(+)-2-AMINO-3-METHOXY-1-PHENYL-1-PROPANOL C27H29Br2NO5NONYLAMINE C26H35Br2NO3 2,5-DICHLOROBENZYLAMINE C24H21Br2Cl2NO32-METHYLCYCLOHEXYLAMINE C24H29Br2NO3 3-METHYLCYCLOHEXYLAMINEC24H29Br2NO3 3-N-PROPOXYPROPYLAMINE C23H29Br2NO4 2,3-DIMETHYLBENZYLAMINEC26H27Br2NO3 3-CHLOROBENZYLAMINE C24H22Br2ClNO34-TERT-BUTYLCYCLOHEXYLAMINE C27H35Br2NO3 (1S,2S)-(+)-THIOMICAMINEC27H29Br2NO5S 2,4-DIMETHYLBENZYLAMINE C26H27Br2NO3 2-AMINOETHYL PHENYLSULFIDE C25H25Br2NO3S PHENETHYLAMINE C25H25Br2NO3 TYRAMINE C25H25Br2NO4L-TYROSINE METHYL ESTER C27H27Br2NO6 BENZHYDRYLAMINE C30H27Br2NO34-METHOXYBENZYLAMINE C25H25Br2NO4 2,3-DICHLOROBENZYLAMINEC24H21Br2Cl2NO3 GLYClNE N-BUTYL ESTER HYDROCHLORIDE C23H27Br2NO5D-(-)-ALPHA-PHENYLGLYClNE ETHYL ESTER C27H27Br2NO5 HYDROCHLORIDE4-CHLORO-2-FLUOROBENZYLAMINE HYDROCHLORIDE C24H21Br2ClFNO3TRANS-2-PHENYLCYCLOPROPYLAMINE C26H25Br2NO3 HYDROCHLORIDE ETHYL4-AMINOBUTYRATE HYDROCHLORIDE C23H27Br2NO5 DL-HOMOCYSTEINE THIOLACTONEHYDROCHLORIDE C21H21Br2NO4S 4-NITROBENZYLAMINE HYDROCHLORIDEC24H22Br2N2O5 NORPHENYLEPHRINE HYDROCHLORIDE C25H25Br2NO5 GLYClNE ETHYLESTER HYDROCHLORIDE C21H23Br2NO5 DL-ALANINE ETHYL ESTER HYDROCHLORIDEC22H25Br2NO5 SARCOSINE ETHYL ESTER HYDROCHLORIDE C22H25Br2NO54-NITRO-N-PROPYLBENZYLAMINE HYDROCHLORIDE C27H28Br2N2O5 PIPERIDINEC22H25Br2NO3 3-METHYLPIPERIDINE C23H27Br2NO33-(HYDROXYMETHYL)-PIPERIDINE C23H27Br2NO4 1,2,3,4-TETRAHYDROISOQUINOLINEC26H25Br2NO3 2-ETHYLPIPERIDINE C24H29Br2NO33,4-DICHLORO-N-ETHYLBENZYLAMINE C26H25Br2Cl2NO3 2-METHYLPYRROLIDINEC22H25Br2NO3 N-ETHYL-N-PROPYLAMINE C22H27Br2NO3 4-METHYLPIPERIDINEC23H27Br2NO3 (S)-(+)-2-(METHOXYMETHYL)PYRROLIDINE C23H27Br2NO4N-BENZYLETHANOLAMINE C26H276r2NO4 DIBENZYLAMINE C31H29Br2NO34-BENZYL-4-HYDROXYPIPERIDINE C29H31Br2NO4 (R)(-)-2-BENZYLAMINO-1-BUTANOLC28H31Br2NO4 N-(N-ETHYLAMINOACETYL)-2,6-DIMETHYLANILINE C29H32Br2N2O4N-ETHYL-O-METHOXYBENZYLAMINE C27H29Br2NO4 MAYBRIDGE NRB 01961C30H33Br2NO5 2-((N-ETHYLAMINO)METHYL)-4-NITROPHENOL C26H26Br2N2O6MAYBRIDGE SEW 01484 C31H29Br2NO4S 3-AZABICYCLO-[3.2.2]NONANEC25H29Br2NO3 N-(2-METHOXY-ETHYL)ETHYLAMINE C22H27Br2NO4


18. The compound as defined in claim 1 which isD-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]valine,D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]leucine,L-S-Benzyl,N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]cysteine,D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]tyrosine,L-N-d-(2,2,5,7,8-Pentamethylchroman-6-sulfonyl),N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]arginine,L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]aminobutyricacid, L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]valine,L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]leucine,L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]proline,L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]cysteine,N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]glycine,L-N-a-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]lysine,D-N-a-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]lysine,N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]aminoisobutyricacid,L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]phenylglycine,D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]phenylglycine,N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]sarcosine,DL-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]-a-methylphenylalanine,L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]isoleucine,D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]methionine,L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]methionine,L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]phenylalanine,D-N-3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]phenylalanine,L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]cyclohexylalanine,L-N-e-(Benzyloxycarbonyl),N-a-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)-benzoyl]lysine,D-N-e-(Benzyloxycarbonyl),N-a-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)-benzoyl]lysine,D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]homoserine,N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]glycine,N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]sarcosine,3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)phenylformylimino diaceticacid,N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]-beta-alanine,N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]-beta-alanine,D-N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylphennoxy)benzoyl]methionine.L-N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]serineD-N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]serineN-[3,5-Dichloro-4-(4-hydroxy-3-bromophenoxy)benzoyl]glycineN-[3,5-Dichloro-4-(4-hydroxy-3-methylphenoxy)benzoyl]glycineN-[3,5-Dichloro-4-(4-hydroxy-3-ethylphenoxy)benzoyl]glycine
 19. Thecompound as defined in claim 1 which isD-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]methionine,L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]methionine,D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]a-methylalanine,D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]aspargine,L-Methyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]alanine,L-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]alanine,L-Dimethyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamate,L-Dimethyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutarnate,L-(O-tert-butyl)methyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamate,L-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamicacid,L-N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]asparticacid,D-di-tert-butyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamate,D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamicacid,L-O-tert-Butyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamine,L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamine,D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamine,L-O-Benzyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]asparticacid,L-O-tert-Butyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]asparagine,L-MethyL-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]homoserine,L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]homoserine,D-Methyl-N-[3,5-dibromo-4-4-hydroxy-3-isopropylphenoxy)phenylacetyl]homoserine,and the compounds showed in the table below,

R Mol Formel L-Val C22H25Br2NO5 L-Val C22H25Br2NO5 L-Tyr C26H25Br2NO6C23H27Br2NO5

C27H27Br2NO5S D-Leu C23H27Br2NO5 D-Tyr C26H25Br2NO6 D-Trp C28H26Br2N2O5L-Arg C23H28Br2N4O5 L-Abu C21H23Br2NO5

C20H21Br2NO5

C20H21Br2NO5 L-Leu C23H27Br2NO5

C25H23Br2NO5 D-Pro C22H23Br2NO5 L-Ile C23H27Br2NO5

C23H25Br2NO5 L-Phe C26H25Br2NO5 L-Lys C23H28Br2N2O5

C23H25Br2NO5 L-Pro C22H23Br2NO5

C25H23Br2NO5


20. The compounds as defined in claim 1 having the structures

or a pharmaceutically acceptable salt or ester(s) thereof.
 21. Thecompounds as defined in claim 1 having the structures

or a pharmaceutically acceptable salt or ester(s) thereof.
 22. Thecompounds as defined in claim 1 having the structures

wherein R₁= isopropyl, methyl, ethyl; R₂ and R₃ may be independentlyselected from Br, Cl and Me; n=0 or 1; R* may be hydrogen, alkyl,cycloalkyl, aryl and heteroaryl; * denotes either D or L stereochemistrywhen R* is not hydrogen; R₅ is hydrogen; and R′ is selected fromhydrogen, lower alky, especially ethyl and methyl.
 23. A method fortreating a disease associated with metabolism dysfunction, or which isdependent on the expression of a T₃ regulated gene, which comprisesadministering to a patient in need of treatment a therapeuticallyeffective amount of a compound as defined in claim
 1. 24. The method asdefined in claim 23 wherein the disease associated with metabolismdysfunction or which is dependent on the expression of a T₃ regulatedgene is obesity, hypercholesterolemia, atherosclerosis, depression,osteoporosis, hypothyroidism, goiter, thyroid cancer, glaucoma, cardiacarrhythmia, congestive heart failure, or skin disorders.
 25. The use ofa compound according to claim 1 in the preparation of a medicament forthe treatment of a disease or disorders which is dependent on theexpression of a T₃ regulated gene.
 26. The use of a compound accordingto claim 1 in which the disease or disorder is selected fromhypothyroidism, hypercholesterolemia, obesity, skin disorders, glaucoma,cardiovascular disease, congestive heart failure and other endocrinedisorders related to thyroid hormone.
 27. A pharmaceutical compositioncomprising an effective amount of a compound according to claim 1 or apharmaceutically effective salt thereof, together with apharmaceutically acceptable carrier.
 28. The method according to claim24 in which the skin disorder or disease is dermal atrophy, postsurgical bruising caused by laser resurfacing, keloids, stria,cellulite, roughened skin, actinic skin damage, lichen planus,ichtyosis, acne, psoriasis, Demier's disease, eczema, atopic dermatitis,chloracne, pityriasis and skin scarring.
 29. A method to treat skindisorder or disease by the use of a compound of claim 1 in combinationwith a retinoid or a vitamin D analog.